PGDH inhibitors and methods of making and using

Abstract

Disclosed herein are compounds that can inhibit 15-hydroxyprostaglandin dehydrogenase. Such compounds may be administered to subjects that may benefit from modulation of prostaglandin levels.

Description

[0001] This application is a continuation of U.S. application Ser. No. 18 / 531,523, filed Dec. 6, 2023, which is a continuation of U.S. application Ser. No. 17 / 725,220, filed Apr. 20, 2022, now U.S. Pat. No. 11,891,389, issued on Feb. 6, 2024, which is a continuation of U.S. application Ser. No. 17 / 484,398, filed Sep. 24, 2021, now U.S. Pat. No. 11,345,702, issued on May 31, 2022, which is a continuation of PCT International Application No. PCT / US2021 / 014783, filed Jan. 22, 2021, which claims the benefit of U.S. Provisional Application No. 62 / 965,062, filed Jan. 23, 2020; U.S. Provisional Application No. 63 / 007,755, filed Apr. 9, 2020; U.S. Provisional Application No. 63 / 029,184, filed May 22, 2020; U.S. Provisional Application No. 63 / 092,116, filed Oct. 15, 2020; U.S. Provisional Application No. 63 / 110,803, filed Nov. 6, 2020; and U.S. Provisional Application No. 63 / 133,965, filed Jan. 5, 2021, each of which is incorporated herein by reference.BACKGROUND OF THE INVENTION

[0002] Prostaglandins are a group of physiologically active lipid compounds with diverse biological effects including vasodilation, inhibition of platelet aggregation, bronchodilation, bronchoconstriction, immune responses, contraction and relaxation of gastrointestinal smooth muscles, gastric acid secretion, gastric mucus secretion, uterus contraction, lipolysis inhibition, neurotransmission, clotting, hyperalgesia, and pyrexia.

[0003] Treatment of diseases or disorders may require activation of prostaglandins, or inhibition of inactivation of prostaglandins. Hydroxyprostaglandin dehydrogenases, such as 15-hydroxyprostaglandin dehydrogenase (15-PGDH) are involved in the inactivation of prostaglandins. As such, diseases / disorders associated with prostaglandins can be prevented, treated and / or managed using inhibitors of hydroxyprostaglandin dehydrogenase such as inhibitors of 15-PGDH.SUMMARY OF THE INVENTION

[0004] In one aspect, provided herein is a method of inhibiting 15-hydroxyprostaglandin dehydrogenase (15-PGDH) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein:

[0006] X is selected from —OCH2—, —C(O)NH—, —NHC(O)—, —C(O)NMe-, —NMeC(O)—, —SCH2—, —S(O)CH2—, —SO2CH2—;

[0007] each Y is independently selected from N and CR11;

[0008] each R1 is independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, —NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;

[0009] R2 is H and R3 is —CF3; or

[0010] R2 and R3 are taken together to form oxo or thio;

[0011] each R4 is independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, —NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;

[0012] each R5 is independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, —NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;

[0013] R6 and R7 are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6 haloalkyl, and C3-10cycloalkyl;

[0014] each R8 is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;

[0015] each R9 is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10 aryl, and 5- to 10-membered heteroaryl;

[0016] each R10 is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3-10cycloalkyl;

[0017] each R11 is independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;

[0018] n is 0, 1, 2, 3, 4, or 5;

[0019] m is 0, 1, 2, 3, or 4; and

[0020] p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

[0021] provided that the compound of Formula I is not

[0022] In some embodiments, the compound is a compound of Formula Ia:or a pharmaceutically acceptable salt thereof.In some embodiments, the compound is a compound of Formula Ib:or a pharmaceutically acceptable salt thereof.In another aspect, provided herein is a method of inhibiting 15-hydroxyprostaglandin dehydrogenase (15-PGDH) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula II:or a pharmaceutically acceptable salt thereof, wherein:T, U, W, X, and Y are independently selected from N and CR5;S, V, and Z are independently selected from N and C;

[0028] R1 is selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; wherein the alkyl, cycloalkyl, aryl, or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, —NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, and 5- to 10-membered heteroaryl;

[0029] R2 is H and R3 is —CF3; or

[0030] R2 and R3 are taken together to form oxo or thio;

[0031] each R4 is independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, —NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; or

[0032] two R4's are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4's are independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, —NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;

[0033] each R5 is independently selected from H, halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, —NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;

[0034] R6 and R7 are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6 haloalkyl, and C3-10cycloalkyl;

[0035] each R8 is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;

[0036] each R9 is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10 aryl, and 5- to 10-membered heteroaryl;

[0037] each R10 is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3-10cycloalkyl; and

[0038] n is 1, 2, 3, or 4; and

[0039] m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;provided that the compound of Formula II is not

[0040] In some embodiments, the compound is a compound of Formula Ha:or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2.In some embodiments, the compound is a compound of Formula IIb: or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2.In some embodiments, the compound is a compound of Formula IIc:or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, 4, or 5.In some embodiments, the compound is a compound of Formula IId:or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.In some embodiments, the compound is a compound of Formula IIe:or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.In some embodiments, the compound is a compound of Formula IIf:or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.In some embodiments, the compound is a compound of Formula IIg:or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.In some embodiments, the compound is a compound of Formula IIh:or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.In some embodiments, the compound is a compound of Formula IIi: or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.In some embodiments, the compound is a compound of Formula IIj:or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.In some embodiments, the compound is a compound of Formula IIn:or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.In some embodiments, the compound is a compound of Formula Up:or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.In another aspect, provided herein is a method of inhibiting 15-hydroxyprostaglandin dehydrogenase (15-PGDH) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula III:or a pharmaceutically acceptable salt thereof, wherein:each X is independently selected from N and CR7;Y is selected from O, S, SO2, and C(R8)2;R1 is selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; wherein the alkyl, cycloalkyl, aryl, or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6 haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;R2 is H and R3 is —CF3; orR2 and R3 are taken together to form oxo or thio;R4 and R5 are independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-10 cycloalkyl; wherein each alkyl, heteroalkyl, haloalkyl, and cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6 haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; orR4 and R5 are taken together, along with the nitrogen atom to which they are attached, to form a 3- to 10-membered heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;each R6 is independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, — NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; ortwo R6's attached to the same carbon atom are taken together to form oxo, thio, or C3-10cycloalkyl, and any remaining R6's are independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6 haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;each R7 is independently selected from H, halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;each R8 is independently selected from H, halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; ortwo R8's can be taken together to form a C3-10cycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;

[0066] R9 and R10 are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6 haloalkyl, and C3-10cycloalkyl;

[0067] each R11 is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;

[0068] each R12 is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10 aryl, and 5- to 10-membered heteroaryl;

[0069] each R13 is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3-10cycloalkyl;

[0070] m is 1 or 2; and

[0071] n is 0, 1, 2, 3, or 4.

[0072] In some embodiments, the compound is a compound of Formula IIIa:or a pharmaceutically acceptable salt thereof.In some embodiments, the compound is a compound of Formula IIIb:or a pharmaceutically acceptable salt thereof, wherein:each R14 is independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10 cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; and

[0076] p is 0, 1, 2, or 3.

[0077] In some embodiments, the compound is a compound of Formula IIIc:or a pharmaceutically acceptable salt thereof.In some embodiments, the compound is a compound of Formula IIId:or a pharmaceutically acceptable salt thereof, wherein:each R14 is independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10 aryl, and 5- to 10-membered heteroaryl; and

[0081] p is 0, 1, 2, or 3.

[0082] In another aspect, provided herein is a compound of Formula IIk:or a pharmaceutically acceptable salt thereof, wherein:

[0084] T, U, and Y are independently selected from N and CR6, provided that when U is N, at least one of T and Y is N;

[0085] R1 is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, —NR7R8, —OR9, —C(O)R9, —C(O)OR9, —C(O)NR7R8, —SOR10, —SO2R10, —SO2NR7R8, —NR11C(O)R9, —NR11C(O)NR7R8, —NR11SO2R9, —NR11SO2NR7R8, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, and 5- to 10-membered heteroaryl;

[0086] R2 is H and R3 is —CF3; or

[0087] R2 and R3 are taken together to form oxo;

[0088] each R4 is independently selected from H and halo;

[0089] R8 is selected from halo, —NR7R8, —OR9, —C(O)R9, —C(O)OR9, —C(O)NR7R8, —SOR10, —SO2R10, —SO2NR7R8, —NR11C(O)R9, —NR11C(O)NR7R8, —NR11SO2R9, —NR11SO2NR7R8, C1-6alkyl, C1-6 heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;

[0090] R6 is selected from H, halo, —NR7R8, —OR9, —C(O)R9, —C(O)OR9, —C(O)NR7R8, —SOR10, —SO2R10, —SO2NR7R8, —NR11C(O)R9, —NR11C(O)NR7R8, —NR11SO2R9, —NR11SO2NR7R8, C1-6alkyl, C1-6 heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;

[0091] R7 and R8 are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6 haloalkyl, and C3-6cycloalkyl;

[0092] each R9 is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;

[0093] each R10 is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, C6-10 aryl, and 5- to 10-membered heteroaryl;

[0094] each R11 is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl; and

[0095] p is 0, 1, or 2.

[0096] In another aspect, provided herein is a compound of Formula IIm:or a pharmaceutically acceptable salt thereof, wherein:

[0098] R1 is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, —NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, and 5- to 10-membered heteroaryl;

[0099] R2 is H and R3 is —CF3; or

[0100] R2 and R3 are taken together to form oxo;

[0101] each R4 is independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, —NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; or

[0102] two R4's are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4's are independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, —NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;

[0103] R8 is selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, —NR10SO2NR6R7, C1-6alkyl, C1-6 heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;

[0104] R6 and R7 are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6 haloalkyl, and C3-10cycloalkyl;

[0105] each R8 is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;

[0106] each R9 is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10 aryl, and 5- to 10-membered heteroaryl;

[0107] each R10 is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3-10 cycloalkyl;

[0108] n is 1, 2, 3, or 4;

[0109] m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and

[0110] p is 0, 1, 2, or 3.

[0111] In another aspect, provided herein is a compound of Formula IIq:or a pharmaceutically acceptable salt thereof, wherein:

[0113] R1 is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, —NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, and 5- to 10-membered heteroaryl;

[0114] R2 is H and R3 is —CF3; or

[0115] R2 and R3 are taken together to form oxo;

[0116] each R4 is independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, —NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; or

[0117] two R4's are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4's are independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR9, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, —NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;

[0118] R5 is selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR9, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, —NR10SO2NR6R7, C1-6alkyl, C1-6 heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;

[0119] R6 and R7 are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6 haloalkyl, and C3-10cycloalkyl;

[0120] each R8 is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;

[0121] each R9 is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;

[0122] each R10 is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3-10 cycloalkyl;

[0123] n is 1, 2, 3, or 4;

[0124] m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and

[0125] p is 0, 1, 2, or 3.

[0126] In another aspect, provided herein is a compound of Formula IIIc:or a pharmaceutically acceptable salt thereof, wherein:

[0128] each X is independently selected from N and CR7;

[0129] Y is selected from O, S, SO2, and C(R8)2;

[0130] R1 is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6 haloalkyl, C3-6cycloalkyl, and 5- to 10-membered heteroaryl;

[0131] R2 is H and R3 is —CF3; or

[0132] R2 and R3 are taken together to form oxo;

[0133] R4 and R5 are independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-6 cycloalkyl; wherein each alkyl, heteroalkyl, haloalkyl, and cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6 haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; or

[0134] R4 and R5 are taken together, along with the nitrogen atom to which they are attached, to form a 3- to 10-membered heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;

[0135] each R6 is independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; or

[0136] two R6's attached to the same carbon atom are taken together to form oxo, and any remaining R6's are independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;

[0137] each R7 and R8 is independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;

[0138] R9 and R10 are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6 haloalkyl, and C3-6cycloalkyl;

[0139] each R11 is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;

[0140] each R12 is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, C6-10 aryl, and 5- to 10-membered heteroaryl;

[0141] each R13 is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C1-6cycloalkyl; and

[0142] n is 0, 1, 2, 3, or 4.

[0143] In another aspect, provided herein is a composition comprising a compound selected from the group consisting of:

[0144] In another aspect, provided herein is a composition comprising a compound selected from the group consisting of: In another aspect, provided herein is a composition comprising a compound selected from the group consisting of: In another aspect, provided herein is a method of promoting and / or stimulation skin pigmentation, comprising administering one or more of the compositions described herein to a subject in need thereof.

[0147] In another aspect, provided herein is a method of inhibiting hair loss, comprising administering one or more of the compositions described herein to a subject in need thereof.

[0148] In another aspect, provided herein is a method of preventing and / or treating skin inflammation and / or damage, comprising administering one or more of the compositions described herein to a subject in need thereof.

[0149] In another aspect, provided herein is a method of preventing and / or treating vascular insufficiency, comprising administering one or more of the compositions described herein to a subject in need thereof.

[0150] In another aspect, provided herein is a method of preventing, treating, minimizing and / or reversing congestive heart failure, cardiomyopathy, comprising administering one or more of the compositions described herein to a subject in need thereof.

[0151] In another aspect, provided herein is a method of reducing cardiac ejection fraction, comprising administering one or more of the compositions described herein to a subject in need thereof.

[0152] In another aspect, provided herein is a method of preventing and / or treating a gastrointestinal disease, comprising administering one or more of the compositions described herein to a subject in need thereof.

[0153] In another aspect, provided herein is a method of preventing and / or treating renal dysfunction, comprising administering one or more of the compositions described herein to a subject in need thereof.

[0154] In another aspect, provided herein is a method of stimulation bone resorption and bone formation, comprising administering one or more of the compositions described herein to a subject in need thereof.

[0155] In another aspect, provided herein is a method of stimulating tissue regeneration by stimulating, comprising administering one or more of the compositions described herein to a subject in need thereof.

[0156] In another aspect, provided herein is a method of modulating cervical ripening, comprising administering one or more of the compositions described herein to a subject in need thereof.

[0157] In another aspect, provided herein is a method of promoting neuroprotection and / or stimulating neuronal regeneration, comprising administering one or more of the compositions described herein to a subject in need thereof.

[0158] In another aspect, provided herein is a method of treating and / or preventing a neurological disorder, a neuropsychiatric disorder, a neural injury, a neural toxicity disorder, a neuropathic pain, or a neural degenerative disorder, comprising administering one or more of the compositions described herein to a subject in need thereof.

[0159] In another aspect, provided herein is a method of treating and / or preventing fibrotic or adhesion disease, disorder or condition, comprising administering one or more of the compositions described herein to a subject in need thereof.

[0160] In another aspect, provided herein is a method of reducing and / or preventing scar formation, comprising administering one or more of the compositions described herein to a subject in need thereof.

[0161] In another aspect, provided herein is a method of treating and / or preventing muscle disorder, muscle injury and / or muscle atrophy, comprising administering one or more of the compositions described herein to a subject in need thereof.

[0162] In another aspect, provided herein is a method of treating and / or preventing fibrosis, comprising administering one or more of the compositions described herein to a subject in need thereof.

[0163] In another aspect, provided herein is a method of treating and / or preventing idiopathic pulmonary fibrosis, comprising administering one or more of the compositions described herein to a subject in need thereof.

[0164] In another aspect, provided herein is a method of treating and / or preventing kidney fibrosis, comprising administering one or more of the compositions described herein to a subject in need thereof.

[0165] In another aspect, provided herein is a method of stimulating muscle regeneration, comprising administering one or more of said compositions described herein to a subject in need thereof.

[0166] In another aspect, provided herein is a method of promoting organ fitness, comprising administering one or more of said compositions described herein to a subject in need thereof.

[0167] In another aspect, provided herein is a method of promoting wound healing, comprising administering one or more of said compositions described herein to a subject in need thereof.

[0168] In another aspect, provided herein is a method of treating acute kidney injury, comprising administering one or more of said compositions described herein to a subject in need thereof.

[0169] In another aspect, provided herein is a method of treating sarcopenia, comprising administering one or more of said compositions described herein to a subject in need thereof.

[0170] In another aspect, provided herein is a method of treating a neuromuscular disease, comprising administering one or more of said compositions of any of the preceding claims to a subject in need thereof.INCORPORATION BY REFERENCE

[0171] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.BRIEF DESCRIPTION OF THE DRAWINGS

[0172] The novel features of the invention are set forth with particularity in the appended claims. An understanding of the features and advantages of the present invention may be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

[0173] FIG. 1 shows results of the cell-based assay for exemplary compounds.DETAILED DESCRIPTION OF THE INVENTIONDefinitions

[0174] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this disclosure belongs.

[0175] As used herein, the singular form “a”, “an” and “the” includes plural references unless the context clearly dictates otherwise.

[0176] The term “Cx-y” when used in conjunction with a chemical moiety, such as alkyl, haloalkyl, or heteroalkyl, is meant to include groups that contain from x to y carbons in the chain. For example, the term “C1-6alkyl” refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from 1 to 6 carbons. The term —Cx-yalkylene—refers to a substituted or unsubstituted alkylene chain with from x to y carbons in the alkylene chain. For example —C1-6alkylene- may be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any one of which is optionally substituted.

[0177] “Alkyl” refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups. An alkyl group may contain from one to twelve carbon atoms (e.g., C1-12 alkyl), such as one to eight carbon atoms (C1-6alkyl) or one to six carbon atoms (C1-6alkyl). Exemplary alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, septyl, octyl, nonyl, and decyl. An alkyl group is attached to the rest of the molecule by a single bond. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more substituents such as those substituents described herein.

[0178] “Haloalkyl” refers to an alkyl group that is substituted by one or more halogens. Exemplary haloalkyl groups include trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, and 1,2-dibromoethyl.

[0179] “Heteroalkyl” refers to a substituted or unsubstituted alkyl group which has one or more skeletal chain atoms selected from an atom other than carbon. Exemplary skeletal chain atoms selected from an atom other than carbon include, e.g., O, N, P, Si, S, or combinations thereof, wherein the nitrogen, phosphorus, and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. If given, a numerical range refers to the chain length in total. For example, a 3- to 8-membered heteroalkyl has a chain length of 3 to 8 atoms. Connection to the rest of the molecule may be through either a heteroatom or a carbon in the heteroalkyl chain. Unless stated otherwise specifically in the specification, a heteroalkyl group is optionally substituted by one or more substituents such as those substituents described herein.

[0180] “Aryl” refers to an aromatic ring wherein each of the atoms forming the ring is a carbon atom. Aryl groups can be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl and naphthyl. In some embodiments, the aryl is phenyl. Depending on the structure, an aryl group can be a monoradical or a diradical (i.e., an arylene group). Unless stated otherwise specifically in the specification, the term “aryl” or the prefix “ar-” (such as in “aralkyl”) is meant to include aryl radicals that are optionally substituted.

[0181] “Heteroaryl” refers to a 3- to 12-membered aromatic ring that comprises at least one heteroatom wherein each heteroatom may be independently selected from N, O, and S. As used herein, the heteroaryl ring may be selected from monocyclic or bicyclic and fused or bridged ring systems wherein at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) π-electron system in accordance with the Hückel theory. The heteroatom(s) in the heteroaryl may be optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl may be attached to the rest of the molecule through any atom of the heteroaryl, valence permitting, such as a carbon or nitrogen atom of the heteroaryl. Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the specification, a heteroaryl is optionally substituted by one or more substituents such as those substituents described herein.

[0182] The term “cycloalkyl” refers to a monocyclic or polycyclic non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom. In some embodiments, cycloalkyls are saturated or partially unsaturated. In some embodiments, cycloalkyls are spirocyclic or bridged compounds. In some embodiments, cycloalkyls are fused with an aromatic ring (in which case the cycloalkyl is bonded through a non-aromatic ring carbon atom). Cycloalkyl groups include groups having from 3 to 10 ring atoms. Representative cycloalkyls include, but are not limited to, cycloalkyls having from three to ten carbon atoms, from three to eight carbon atoms, from three to six carbon atoms, or from three to five carbon atoms. Monocyclic cycloalkyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic radicals include, for example, adamantyl, 1,2-dihydronaphthalenyl, 1,4-dihydronaphthalenyl, tetrainyl, decalinyl, 3,4-dihydronaphthalenyl-1(2H)-one, spiro[2.2]pentyl, norbornyl and bicycle[1.1.1]pentyl. Unless otherwise stated specifically in the specification, a cycloalkyl group may be optionally substituted.

[0183] The term “heterocycloalkyl” refers to a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen, and sulfur. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, or bicyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom) or bridged ring systems. The nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidized. The nitrogen atom may be optionally quaternized. The heterocycloalkyl radical may be partially or fully saturated. Examples of heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl. The term heterocycloalkyl also includes all ring forms of carbohydrates, including but not limited to monosaccharides, disaccharides and oligosaccharides. Unless otherwise noted, heterocycloalkyls have from 2 to 12 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e. skeletal atoms of the heterocycloalkyl ring). Unless stated otherwise specifically in the specification, a heterocycloalkyl group may be optionally substituted.

[0184] The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons or heteroatoms of the structure. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, the heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. Substituents can include any substituents described herein, for example, an oxo, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, a carbocycle, a heterocycle, a cycloalkyl, a heterocycloalkyl, an aromatic and heteroaromatic moiety.

[0185] It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate. Unless specifically stated as “unsubstituted,” references to chemical moieties herein are understood to include substituted variants. For example, reference to a “heteroaryl” group or moiety implicitly includes both substituted and unsubstituted variants.

[0186] Where substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., —CH2O— is equivalent to —OCH2—.

[0187] “Optional” or “optionally” means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, “optionally substituted aryl” means that the aryl group may or may not be substituted and that the description includes both substituted aryl groups and aryl groups having no substitution.

[0188] Compounds of the present disclosure also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.

[0189] The compounds described herein may exhibit their natural isotopic abundance, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure. For example, hydrogen has three naturally occurring isotopes, denoted 1H (protium), 2H (deuterium), and 3H (tritium). Protium is the most abundant isotope of hydrogen in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increased in vivo half-life and / or exposure, or may provide a compound useful for investigating in vivo routes of drug elimination and metabolism.

[0190] Isotopically-enriched compounds may be prepared by conventional techniques well known to those skilled in the art.

[0191] “Isomers” are different compounds that have the same molecular formula. “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space. “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a “racemic” mixture. The term “(f)” is used to designate a racemic mixture where appropriate. “Diastereoisomers” or “diastereomers” are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified by either R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (−) depending on the direction (dextro- or levorotatory) in which they rotate plane polarized light at the wavelength of the sodium D line.

[0192] Certain compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, the asymmetric centers of which can be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The present chemical entities, pharmaceutical compositions and methods are meant to include all such possible stereoisomers, including racemic mixtures, optically pure forms, mixtures of diastereomers and intermediate mixtures. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. The optical activity of a compound can be analyzed via any suitable method, including but not limited to chiral chromatography and polarimetry, and the degree of predominance of one stereoisomer over the other isomer can be determined.

[0193] Chemical entities having carbon-carbon double bonds or carbon-nitrogen double bonds may exist in Z- or E-form (or cis- or trans-form). Furthermore, some chemical entities may exist in various tautomeric forms. Unless otherwise specified, chemical entities described herein are intended to include all Z-, E- and tautomeric forms as well.

[0194] Isolation and purification of the chemical entities and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography or thick-layer chromatography, or a combination of these procedures. Specific illustrations of suitable separation and isolation procedures can be had by reference to the examples herein below. However, other equivalent separation or isolation procedures can also be used.

[0195] When stereochemistry is not specified, certain small molecules described herein include, but are not limited to, when possible, their isomers, such as enantiomers and diastereomers, mixtures of enantiomers, including racemates, mixtures of diastereomers, and other mixtures thereof, to the extent they can be made by one of ordinary skill in the art by routine experimentation. In those situations, the single enantiomers or diastereomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution of the racemates or mixtures of diastereomers. Resolution of the racemates or mixtures of diastereomers, if possible, can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example, a chiral high-pressure liquid chromatography (HPLC) column. Furthermore, a mixture of two enantiomers enriched in one of the two can be purified to provide further optically enriched form of the major enantiomer by recrystallization and / or trituration. In addition, such certain small molecules include Z- and E-forms (or cis- and trans-forms) of certain small molecules with carbon-carbon double bonds or carbon-nitrogen double bonds. Where certain small molecules described herein exist in various tautomeric forms, the term “certain small molecule” is intended to include all tautomeric forms of the certain small molecule.

[0196] The term “salt” or “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.

[0197] The phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

[0198] The term “effective amount” or “therapeutically effective amount” refers to that amount of a compound described herein that is sufficient to affect the intended application, including but not limited to disease treatment, as defined below. The therapeutically effective amount may vary depending upon the intended treatment application (in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. The term also applies to a dose that may induce a particular response in target cells, e.g., reduction of platelet adhesion and / or cell migration. The specific dose may vary depending on the particular compounds chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.

[0199] As used herein, “treatment” or “treating” refers to an approach for obtaining beneficial or desired results with respect to a disease, disorder, or medical condition including but not limited to a therapeutic benefit and / or a prophylactic benefit. A therapeutic benefit can include, for example, the eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit can include, for example, the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder. In certain embodiments, for prophylactic benefit, the compositions are administered to a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made.

[0200] A “therapeutic effect,” as that term is used herein, encompasses a therapeutic benefit and / or a prophylactic benefit as described above. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0201] The term “co-administration,”“administered in combination with,” and their grammatical equivalents, as used herein, encompass administration of two or more agents to an animal, including humans, so that both agents and / or their metabolites are present in the subject at the same time. Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which both agents are present.

[0202] The terms “antagonist” and “inhibitor” are used interchangeably, and they refer to a compound having the ability to inhibit a biological function (e.g., activity, expression, binding, protein-protein interaction) of a target protein or enzyme. Accordingly, the terms “antagonist” and “inhibitor” are defined in the context of the biological role of the target protein. While preferred antagonists herein specifically interact with (e.g., bind to) the target, compounds that inhibit a biological activity of the target protein by interacting with other members of the signal transduction pathway of which the target protein is a member are also specifically included within this definition.

[0203] A preferred biological activity inhibited by an antagonist is associated with the development, growth, or spread of a tumor.

[0204] Whenever a protein is referred to herein, it will be understood that a single protein can be referred to by different names. For example, “15-PGDH”, “PGDH”, and “hPGDH” all refer to the same protein, 15-hydroxyprostaglandin dehydrogenase.Methods of Inhibiting 15-PGDH

[0205] Provided herein are methods of inhibiting 15-hydroxyprostaglandin dehydrogenase (15-PGDH).

[0206] In one aspect, provided herein is a method of inhibiting 15-hydroxyprostaglandin dehydrogenase (15-PGDH) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I:or a pharmaceutically acceptable salt thereof, wherein:

[0208] X is selected from —OCH2—, —C(O)NH—, —NHC(O)—, —C(O)NMe-, —NMeC(O)—, —SCH—, —S(O)CH2—, —SO2CH2—;

[0209] each Y is independently selected from N and CR11;

[0210] each R1 is independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, —NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;

[0211] R2 is H and R3 is —CF3; or

[0212] R2 and R3 are taken together to form oxo or thio;

[0213] each R4 is independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, —NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;

[0214] each R5 is independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, —NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;

[0215] R6 and R7 are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6 haloalkyl, and C3-10cycloalkyl;

[0216] each R8 is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;

[0217] each R9 is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10 aryl, and 5- to 10-membered heteroaryl;

[0218] each R10 is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3-10cycloalkyl; each R11 is independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, —NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;

[0219] n is 0, 1, 2, 3, 4, or 5;

[0220] m is 0, 1, 2, 3, or 4; and

[0221] p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

[0222] provided that the compound of Formula I is not

[0223] In some embodiments, X is selected from —OCH2—, —C(O)NH—, —NHC(O)—, —C(O)NMe-, —NMeC(O)—, —SCH2—, —S(O)CH2—, and —SO2CH2—. In some embodiments, X is —OCH2—. In some embodiments, X is —C(O)NH—. In some embodiments, X is —NHC(O)—. In some embodiments, X is —C(O)NMe-. In some embodiments, X is —NMeC(O)—. In some embodiments, X is —SCH2—. In some embodiments, X is —S(O)CH2—. In some embodiments, X is —SO2CH2—.

[0224] In some embodiments, each Y is independently selected from N and CR11. In some embodiments, each Y is N. In some embodiments, each Y is CR11. In some embodiments, one Y is N and the other Y is CR11.

[0225] In some embodiments, each R1 is independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, —NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R1 is independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, and —NR10SO2NR6R7. In some embodiments, each R1 is independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, and —NR10SO2NR6R7. In some embodiments, each R1 is independently selected from halo, —NR6R7, —OR8, —C(O)R9, and —C(O)OR9.

[0226] In some embodiments, R2 is H and R3 is —CF3. In some embodiments, R2 and R3 are taken together to form oxo. In some embodiments, R2 and R3 are taken together to form thio.

[0227] In some embodiments, each R4 is independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, —NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R4 is independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, and —NR10SO2NR6R7. In some embodiments, each R4 is independently selected from halo, —NR6R7, —OR8, —C(O)R9, —C(O)OR8, —C(O)NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, and —NR10SO2NR6R7. In some embodiments, each R4 is independently selected from halo, —NR6R7, —OR8, —C(O)R8, and —C(O)OR8.

[0228] In some embodiments, each R5 is independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, —NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R5 is independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, and —NR10SO2NR6R7. In some embodiments, each R5 is independently selected from halo, —NR6R7, —OR8, —C(O)R9, —C(O)OR8, —C(O)NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, and —NR10SO2NR6R7. In some embodiments, each R5 is independently selected from halo, —NR6R7, —OR8, —C(O)R8, and —C(O)OR8.

[0229] In some embodiments, R6 and R7 are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl. In some embodiments, R6 and R7 are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, R6 and R7 are independently selected at each occurrence from H, and C1-6alkyl.

[0230] In some embodiments, each R8 is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R8 is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl. In some embodiments, each R8 is independently selected from H, C1-6alkyl, C1-6 heteroalkyl, and C1-6haloalkyl. In some embodiments, each R8 is independently selected from H, and C1-6alkyl.

[0231] In some embodiments, each R9 is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6 haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R9 is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl. In some embodiments, each R9 is independently selected from C1-6alkyl, C1-6heteroalkyl, and C1-6 haloalkyl. In some embodiments, each R9 is independently selected from C1-6alkyl.

[0232] In some embodiments, each R10 is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3-10cycloalkyl. In some embodiments, each R10 is independently selected from H, C1-6alkyl, and C1-6haloalkyl. In some embodiments, each R10 is independently selected from H and C1-6alkyl.

[0233] In some embodiments, each R11 is independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, —NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R11 is independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, and —NR10SO2NR6R7.

[0234] In some embodiments, each R11 is independently selected from halo, —NR6R7, —OR8, —C(O)R9, —C(O)OR8, —C(O)NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, and —NR10SO2NR6R7. In some embodiments, each R11 is independently selected from halo, —NR6R7, —OR8, —C(O)R9, and —C(O)OR8.

[0235] In some embodiments, n is 0, 1, 2, 3, 4, or 5. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4. In some embodiments, n is 5.

[0236] In some embodiments, m is 0, 1, 2, 3, or 4. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4.

[0237] In some embodiments, p is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5. In some embodiments, p is 6. In some embodiments, p is 7. In some embodiments, p is 8. In some embodiments, p is 9. In some embodiments, p is 10.

[0238] In some embodiments, the compound is a compound of Formula Ia: or a pharmaceutically acceptable salt thereof.In some embodiments, the compound is a compound of Formula Ib:or a pharmaceutically acceptable salt thereof.In another aspect, provided herein is a method of inhibiting 15-hydroxyprostaglandin dehydrogenase (15-PGDH) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula II:or a pharmaceutically acceptable salt thereof, wherein:T, U, W, X, and Y are independently selected from N and CR5;S, V, and Z are independently selected from N and C;

[0244] R1 is selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10 cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; wherein the alkyl, cycloalkyl, aryl, or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, —NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, and 5- to 10-membered heteroaryl;

[0245] R2 is H and R3 is —CF3; or

[0246] R2 and R3 and are taken together to form oxo or thio;

[0247] each R4 is independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R, —NR10C(O)NR6R7, —NR10SO2R8, —NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10 aryl, and 5- to 10-membered heteroaryl; or

[0248] two R4's are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4's are independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, —NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;

[0249] each R5 is independently selected from H, halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, —NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;

[0250] R6 and R7 are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6 haloalkyl, and C3-10cycloalkyl;

[0251] each R8 is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;

[0252] each R9 is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10 aryl, and 5- to 10-membered heteroaryl;

[0253] each R10 is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3-10cycloalkyl; and

[0254] n is 1, 2, 3, or 4; and

[0255] m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

[0256] provided that the compound of Formula II is not

[0257] In some embodiments, T, U, W, X, and Y are independently selected from N and CR5. In some embodiments, at least one of T, U, W, X, and Y is N and the rest are CR5. In some embodiments, at least two of T, U, W, X, and Y are N and the rest are CR5. In some embodiments, at least three of T, U, W, X, and Y are N and the rest are CR5. In some embodiments, at least four of T, U, W, X, and Y are N and the rest are CR5. In some embodiments, T, U, W, X, and Y are CR5. In some embodiments, T, U, W, X, and Y are N.

[0258] In some embodiments, S, V, and Z are independently selected from N and C. In some embodiments, at least one of S, V, and Z is N and the rest are C. In some embodiments, at least two of S, V, and Z are N and the rest are C. In some embodiments, S, V, and Z are N. In some embodiments, S, V, and Z are C.

[0259] In some embodiments, R1 is selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; wherein the alkyl, cycloalkyl, aryl, or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, —NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, and 5- to 10-membered heteroaryl. In some embodiments, R1 is selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; wherein the alkyl, aryl, or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, —NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, and 5- to 10-membered heteroaryl. In some embodiments, R1 is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR9, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, —NR10SO2NR6R7, C1-6 alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, and 5- to 10-membered heteroaryl. In some embodiments, R1 is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, and —NR10SO2NR6R7. In some embodiments, R1 is selected from C6-10 aryl and 5- to 10-membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)ORS, and —C(O)NR6R7.

[0260] In some embodiments, R2 is H and R3 is —CF3. In some embodiments, R2 and R3 are taken together to form oxo. In some embodiments, R2 and R3 are taken together to form thio.

[0261] In some embodiments, each R4 is independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, —NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R4 is independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, —NR10SO2NR6R7, C1-6 alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R4 is independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, and —NR10SO2NR6R7. In some embodiments, each R4 is independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, and —C(O)NR6R7. In some embodiments, each R4 is halo. In some embodiments, each R4 is fluoro.

[0262] In some embodiments, two R4's are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4's are independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, —NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, two R4's are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4's are independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, —NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, two R4's are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4's are independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, and —NR10SO2NR6R7. In some embodiments, two R4's are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4's are independently selected from halo, —NR6R7, —OR11, —C(O)R11, —C(O)OR11, and —C(O)NR6R7. In some embodiments, two R4's are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4's are independently selected from halo. In some embodiments, two R4's are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4's are fluoro.

[0263] In some embodiments, each R5 is independently selected from H, halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, —NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R5 is independently selected from H, halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, —NR10SO2NR6R7, C1-6 alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R5 is independently selected from H, halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, and —NR10SO2NR6R7. In some embodiments, each R5 is independently selected from H, halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, and —C(O)NR6R7. In some embodiments, each R5 is independently selected from H and halo.

[0264] In some embodiments, R6 and R7 are independently selected at each occurrence from H, C1-6 alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl. In some embodiments, R6 and R7 are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, R6 and R7 are independently selected at each occurrence from H and C1-6alkyl.

[0265] In some embodiments, each R8 is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R8 is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl. In some embodiments, each R8 is independently selected from H, C1-6alkyl, C1-6 heteroalkyl, and C1-6haloalkyl. In some embodiments, each R8 is independently selected from H and C1-6alkyl.

[0266] In some embodiments, each R9 is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6 haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R9 is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl. In some embodiments, each R9 is independently selected from C1-6alkyl, C1-6heteroalkyl, and C1-6 haloalkyl. In some embodiments, each R9 is independently selected from C1-6alkyl.

[0267] In some embodiments, each R10 is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3-10cycloalkyl. In some embodiments, each R10 is independently selected from H, C1-6alkyl, and C1-6haloalkyl. In some embodiments, each R10 is independently selected from H and C1-6alkyl.

[0268] In some embodiments, n is 1, 2, 3, or 4. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0269] In some embodiments, m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 6. In some embodiments, m is 7. In some embodiments, m is 8. In some embodiments, m is 9. In some embodiments, m is 10.

[0270] In some embodiments, the compound is a compound of Formula IIa:or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2.In some embodiments, p is 0, 1, or 2. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2.

[0272] In some embodiments, the compound is a compound of Formula IIb:or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2.In some embodiments, p is 0, 1, or 2. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2.

[0274] In some embodiments, the compound is a compound of Formula IIc:or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, 4, or 5.In some embodiments, p is 0, 1, 2, 3, 4, or 5. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4. In some embodiments, p is 5.

[0276] In some embodiments, the compound is a compound of Formula IId:or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.In some embodiments, p is 0, 1, 2, 3, or 4. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4.

[0278] In some embodiments, the compound is a compound of Formula IIe:or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.In some embodiments, p is 0, 1, 2, 3, or 4. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4.

[0280] In some embodiments, the compound is a compound of Formula IIf:or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.

[0282] In some embodiments, the compound is a compound of Formula IIg:or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.In some embodiments, p is 0, 1, 2, 3, or 4. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4.

[0284] In some embodiments, the compound is a compound of Formula IIh:or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.

[0286] In some embodiments, the compound is a compound of Formula IIi: or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.In some embodiments, p is 0, 1, 2, 3, or 4. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4.

[0288] In some embodiments, the compound is a compound of Formula IIj:or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.

[0290] In some embodiments, the compound is a compound of Formula IIn:or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, or 3.In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.

[0292] In some embodiments, the compound is a compound of Formula Ip: or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, 2, 3, or 4.In some embodiments, p is 0, 1, 2, 3, or 4. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3. In some embodiments, p is 4.

[0294] In another aspect, provided herein is a method of inhibiting 15-hydroxyprostaglandin dehydrogenase (15-PGDH) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula III:or a pharmaceutically acceptable salt thereof, wherein:

[0296] each X is independently selected from N and CR7;

[0297] Y is selected from O, S, SO2, and C(R8)2;

[0298] R1 is selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; wherein the alkyl, cycloalkyl, aryl, or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6 haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;

[0299] R2 is H and R3 is —CF3; or

[0300] R2 and R3 are taken together to form oxo or thio;

[0301] R4 and R5 are independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl; wherein each alkyl, heteroalkyl, haloalkyl, and cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; or

[0302] R4 and R5 are taken together, along with the nitrogen atom to which they are attached, to form a 3- to 10-membered heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;

[0303] each R6 is independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; or

[0304] two R6's attached to the same carbon atom are taken together to form oxo, thio, or C3-10cycloalkyl, and any remaining R6's are independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6 haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;

[0305] each R7 is independently selected from H, halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;

[0306] each R8 is independently selected from H, halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; or

[0307] two R8's can be taken together to form a C3-10cycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;

[0308] R9 and R10 are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6 haloalkyl, and C3-10cycloalkyl;

[0309] each R11 is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;

[0310] each R12 is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;

[0311] each R13 is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3-10cycloalkyl;

[0312] m is 1 or 2; and

[0313] n is 0, 1, 2, 3, or 4.

[0314] In some embodiments, each X is independently selected from N and CR7. In some embodiments, at least one X is N and the rest are CR7. In some embodiments, at least two X are N and the rest are CR7. In some embodiments, each X is N. In some embodiments, each X is CR7.

[0315] In some embodiments, Y is selected from O, S, SO2, and C(R8)2. In some embodiments, Y is O. In some embodiments, Y is S. In some embodiments, Y is SO2. In some embodiments, Y is C(R8)2.

[0316] In some embodiments, R1 is selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; wherein the alkyl, cycloalkyl, aryl, or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, R1 is selected from C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; wherein the cycloalkyl, aryl, or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, R1 is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10 cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, R1 is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, — NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, R1 is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, and —NR13SO2NR9R10. In some embodiments, R1 is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, and —C(O)NR9R10.

[0317] In some embodiments, R2 is H and R3 is —CF3. In some embodiments, R2 and R3 are taken together to form oxo. In some embodiments, R2 and R3 are taken together to form thio.

[0318] In some embodiments, R4 and R5 are independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl; wherein each alkyl, heteroalkyl, haloalkyl, and cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6 haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, R4 and R5 are independently selected from C3-10cycloalkyl; wherein each cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR1l, —C(O)NR9R10, —SOR2, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6 alkyl, C1-6heteroalkyl, C1-6-haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, R4 and R5 are independently selected from C3-10cycloalkyl; wherein each cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, R4 and R5 are independently selected from C3-10cycloalkyl; wherein each cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, and —NR13SO2NR9R10. In some embodiments, R4 and R5 are independently selected from C3-10cycloalkyl; wherein each cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, and —C(O)NR9R10.

[0319] In some embodiments, R4 and R5 are taken together, along with the nitrogen atom to which they are attached, to form a 3- to 10-membered heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, R4 and R5 are taken together, along with the nitrogen atom to which they are attached, to form a 3- to 10-membered heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, R4 and R5 are taken together, along with the nitrogen atom to which they are attached, to form a 3- to 10-membered heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, and —NR13SO2NR9R10. In some embodiments, R4 and R5 are taken together, along with the nitrogen atom to which they are attached, to form a 3- to 10-membered heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, and —C(O)NR9R10.

[0320] In some embodiments, each R6 is independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R6 is independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R6 is independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R11, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, and —NR13SO2NR9R10. In some embodiments, each R6 is independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, and —C(O)NR9R10.

[0321] In some embodiments, two R6's attached to the same carbon atom are taken together to form oxo, thio, or C3-10cycloalkyl, and any remaining R6's are independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, two R6's attached to the same carbon atom are taken together to form oxo, thio, or C3-10cycloalkyl, and any remaining R6's are independently selected from halo, —NR9R10, —OR111, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, two R6's attached to the same carbon atom are taken together to form oxo, thio, or C3-10cycloalkyl, and any remaining R6's are independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, and —NR13SO2NR9R10. In some embodiments, two R6's attached ID the same carbon atom are taken together to form oxo, thio, or C3-10 cycloalkyl, and any remaining R6's are independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, and —C(O)NR9R10.

[0322] In some embodiments, each R7 is independently selected from H, halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R7 is independently selected from H, halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R7 is independently selected from H, halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, and —NR13SO2NR9R10. In some embodiments, each R7 is independently selected from H, halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, and —C(O)NR9R10.

[0323] In some embodiments, each R8 is independently selected from H, halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R8 is independently selected from H, halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R8 is independently selected from H, halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, and —NR13SO2NR9R10. In some embodiments, each R8 is independently selected from H, halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, and —C(O)NR9R10.

[0324] In some embodiments, two R8's can be taken together to form a C3-10cycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, two R8's can be taken together to form a C3-10cycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, two R8's can be taken together to form a C3-10cycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR2, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, and —NR13SO2NR9R10. In some embodiments, two R8's can be taken together to form a C3-10cycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, and —C(O)NR9R10.

[0325] In some embodiments, R9 and R10 are independently selected at each occurrence from H, C1-6 alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-10 cycloalkyl. In some embodiments, R9 and R10 are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, R9 and R10 are independently selected at each occurrence from H and C1-6alkyl.

[0326] In some embodiments, each R11 is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R11 is independently selected from H, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R11 is independently selected from H and C1-6alkyl.

[0327] In some embodiments, each R12 is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6 haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R12 is independently selected from C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R12 is independently selected from C1-6alkyl.

[0328] In some embodiments, each R13 is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3-10cycloalkyl. In some embodiments, each R13 is independently selected from H, C1-6alkyl, and C1-6haloalkyl. In some embodiments, each R13 is independently selected from H and C1-6alkyl.

[0329] In some embodiments, m is 1 or 2. In some embodiments, m is 1. In some embodiments, m is 2.

[0330] In some embodiments, n is 0, 1, 2, 3, or 4. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0331] In some embodiments, the compound is a compound of Formula IIIa:or a pharmaceutically acceptable salt thereof.In some embodiments, the compound is a compound of Formula IIIb:or a pharmaceutically acceptable salt thereof, wherein:each R14 is independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; and

[0335] p is 0, 1, 2, or 3.

[0336] In some embodiments, each R14 is independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10 cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R14 is independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R14 is independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, and —NR13SO2NR9R10. In some embodiments, each R14 is independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, and —C(O)NR9R10. In some embodiments, each R14 is independently halo. In some embodiments, each R14 is independently fluoro.

[0337] In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.

[0338] In some embodiments, the compound is a compound of Formula IIIc:or a pharmaceutically acceptable salt thereof.In some embodiments, the compound is a compound of Formula IIId:or a pharmaceutically acceptable salt thereof, wherein:each R14 is independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10 cycloalkyl, C6-10 aryl, and 5- to 10-membered heteroaryl; and

[0342] p is 0, 1, 2, or 3.

[0343] In some embodiments, each R14 is independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R14 is independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R14 is independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, and —NR13SO2NR9R10. In some embodiments, each R14 is independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, and —C(O)NR9R10. In some embodiments, each R14 is independently halo. In some embodiments, each R14 is independently fluoro.

[0344] In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.Compounds

[0345] In one aspect, provided herein is a compound of Formula IIk:or a pharmaceutically acceptable salt thereof, wherein:

[0347] T, U, and Y are independently selected from N and CR6, provided that when U is N, at least one of T and Y is N;

[0348] R1 is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, —NR7R8, —OR9, —C(O)R9, —C(O)OR9, —C(O)NR7R8, —SOR10, —SO2R10, —SO2NR7R8, —NR11C(O)R9, —NR11C(O)NR7R8, —NR11SO2R9, —NR11SO2NR7R8, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, and 5- to 10-membered heteroaryl;

[0349] R2 is H and R3 is —CF3; or

[0350] R2 and R3 are taken together to form oxo;

[0351] each R4 is independently selected from H and halo;

[0352] R5 is selected from halo, —NR7R8, —OR9, —C(O)R9, —C(O)OR9, —C(O)NR7R8, —SOR10, —SO2R10, —SO2NR7R8, —NR11C(O)R9, —NR11C(O)NR7R8, —NR11SO2R9, —NR11SO2NR7R8, C1-6alkyl, C1-6 heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;

[0353] R6 is selected from H, halo, —NR7R8, —OR9, —C(O)R9, —C(O)OR9, —C(O)NR7R8, —SOR10, —SO2R10, —SO2NR7R8, —NR11C(O)R9, —NR11C(O)NR7R8, —NR11SO2R9, —NR11SO2NR7R8, C1-6alkyl, C1-6 heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;

[0354] R7 and R8 are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6 haloalkyl, and C3-6cycloalkyl;

[0355] each R9 is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;

[0356] each R10 is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, C6-10 aryl, and 5- to 10-membered heteroaryl;

[0357] each R11 is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl; and

[0358] p is 0, 1, or 2.

[0359] In some embodiments, T, U, and Y are independently selected from N and CR6, provided that when U is N, at least one of T and Y is N. In some embodiments, one of T, U, and Y is N and the rest are CR6. In some embodiments, two of T, U, and Y are N and the rest are CR6. In some embodiments, one of T, U, and Y is CR6 and the rest are N. In some embodiments, two of T, U, and Y are CR6 and the rest are N. In some embodiments, T, U, and Y are N. In some embodiments, T, U, and Y are CR6.

[0360] In some embodiments, R1 is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, —NR7R8, —OR9, —C(O)R9, —C(O)OR9, —C(O)NR7R8, —SOR10, —SO2R10, —SO2NR7R8, —NR11C(O)R9, —NR11C(O)NR7R8, —NR11SO2R9, —NR11SO2NR7R8, C1-6alkyl, C1-6 heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, and 5- to 10-membered heteroaryl. In some embodiments, R1 is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, —NR7R8, —OR9, —C(O)R9, —C(O)OR9, —C(O)NR7R8, —SOR10, —SO2R10, —SO2NR7R8, —NR11C(O)R9, —NR11C(O)NR7R8, —NR11SO2R9, —NR11SO2NR7R8, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, R1 is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, —NR7R8, —OR9, —C(O)R9, —C(O)OR9, —C(O)NR7R8, —SOR10, —SO2R10, —SO2NR7R8, —NR11C(O)R9, —NR11C(O)NR7R8, —NR11SO2R9, and —NR11SO2NR7R8. In some embodiments, R1 is selected from C6-10 aryl and 5- to 10-membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, —NR7R8, —OR9, —C(O)R9, —C(O)OR9, and —C(O)NR7R8.

[0361] In some embodiments, R2 is H and R3 is —CF3. In some embodiments, R2 and R3 are taken together to form oxo.

[0362] In some embodiments, each R4 is independently selected from H and halo. In some embodiments, each R4 is independently selected from H and fluoro. In some embodiments, each R4 is H. In some embodiments, each R4 is fluoro. In some embodiments, one R4 is H and one R4 is fluoro.

[0363] In some embodiments, R5 is selected from halo, —NR7R8, —OR9, —C(O)R9, —C(O)OR9, —C(O)NR7R8, —SOR10, —SO2R10, —SO2NR7R8, —NR11C(O)R9, —NR11C(O)NR7R8, —NR11SO2R9, —NR11SO2NR7R8, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, R5 is selected from halo, —NR7R8, —OR9, —C(O)R9, —C(O)OR9, —C(O)NR7R8, —SOR10, —SO2R10, —SO2NR7R8, —NR11C(O)R9, —NR11C(O)NR7R8, —NR11SO2R9, —NR11SO2NR7R8, C1-6alkyl, C1-6heteroalkyl, and C1-6 haloalkyl. In some embodiments, R5 is selected from halo, —NR7R8, —OR9, —C(O)R9, —C(O)OR9, —C(O)NR7R8, —SOR10, —SO2R10, —SO2NR7R8, —NR11C(O)R9, —NR11C(O)NR7R8, —NR11SO2R9, and —NR11SO2NR7R8. In some embodiments, R5 is selected from halo, —NR7R8, —OR9, —C(O)R9, —C(O)OR9, and —C(O)NR7R8.

[0364] In some embodiments, R6 is selected from H, halo, —NR7R8, —OR9, —C(O)R9, —C(O)OR9, —C(O)NR7R8, —SOR10, —SO2R10, —SO2NR7R8, —NR11C(O)R9, —NR11C(O)NR7R8, —NR11SO2R9, —NR11SO2NR7R8, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, R6 is selected from H, halo, —NR7R8, —OR9, —C(O)R9, —C(O)OR9, —C(O)NR7R8, —SOR10, —SO2R10, —SO2NR7R8, —NR11C(O)R9, —NR11C(O)NR7R8, —NR11SO2R9, —NR11SO2NR7R8, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, R6 is selected from H, halo, —NR7R8, —OR9, —C(O)R9, —C(O)OR9, —C(O)NR7R8, —SOR10, —SO2R10, —SO2NR7R8, —NR11C(O)R9, —NR11C(O)NR7R8, —NR11SO2R9, and — NR11SO2NR7R8. In some embodiments, R6 is selected from H, halo, —NR7R8, —OR9, —C(O)R9, —C(O)OR9, and —C(O)NR7R8.

[0365] In some embodiments, R7 and R8 are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-6cycloalkyl. In some embodiments, R7 and R8 are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, R7 and R8 are independently selected at each occurrence from H and C1-6alkyl.

[0366] In some embodiments, each R9 is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R9 is independently selected from H, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R9 is independently selected from H and C1-6alkyl.

[0367] In some embodiments, each R10 is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6 haloalkyl, C3-6cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R10 is independently selected from C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R10 is independently selected from C1-6alkyl.

[0368] In some embodiments, each R11 is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl. In some embodiments, each R11 is independently selected from H, C1-6alkyl, and C1-6haloalkyl. In some embodiments, each R11 is independently selected from H and C1-6alkyl.

[0369] In some embodiments, p is 0, 1, or 2. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2.

[0370] In another aspect, provided herein is a compound of Formula IIm:or a pharmaceutically acceptable salt thereof, wherein:

[0372] R1 is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, —NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, and 5- to 10-membered heteroaryl;

[0373] R2 is H and R3 is —CF3; or

[0374] R2 and R3 are taken together to form oxo;

[0375] each R4 is independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, —NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; or

[0376] two R4's are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4's are independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, —NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;

[0377] R5 is selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, —NR10SO2NR6R7, C1-6alkyl, C1-6 heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;

[0378] R6 and R7 are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6 haloalkyl, and C3-10cycloalkyl;

[0379] each R8 is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;

[0380] each R9 is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10 aryl, and 5- to 10-membered heteroaryl;

[0381] each R10 is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3-10cycloalkyl;

[0382] n is 1, 2, 3, or 4;

[0383] m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and

[0384] p is 0, 1, 2, or 3.

[0385] In some embodiments, R1 is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, —NR10SO2NR6R7, C1-6alkyl, C1-6 heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, and 5- to 10-membered heteroaryl. In some embodiments, R1 is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, — NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, —NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, R1 is selected from C6-10 aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, and —NR10SO2NR6R7. In some embodiments, R1 is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, and —C(O)NR6R7.

[0386] In some embodiments, R2 is H and R3 is —CF3. In some embodiments, R2 and R3 are taken together to form oxo.

[0387] In some embodiments, each R4 is independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, —NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R4 is independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR9, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, —NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, and C1-6 haloalkyl. In some embodiments, each R4 is independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, and —NR10SO2NR6R7. In some embodiments, each R4 is independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR9, and —C(O)NR6R7. In some embodiments, each R4 is independently selected from halo. In some embodiments, each R4 is fluoro.

[0388] In some embodiments, two R4's are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4's are independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR9, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, —NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10 aryl, and 5- to 10-membered heteroaryl. In some embodiments, two R4's are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4's are independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR9, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, —NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, and C1-6 haloalkyl. In some embodiments, two R4's are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4's are independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, and —NR10SO2NR6R7. In some embodiments, two R4's are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4's are independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, and —C(O)NR6R7.

[0389] In some embodiments, R5 is selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, —NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, R5 is selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, —NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, and C1-6 haloalkyl. In some embodiments, R5 is selected from halo, —NR6R7, —OR8, —C(O)R9, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, and —NR10SO2NR6R7. In some embodiments, R5 is selected from halo, —NR6R7, —OR8, —C(O)R9, —C(O)OR9, and —C(O)NR6R7.

[0390] In some embodiments, R6 and R7 are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl. In some embodiments, R6 and R7 are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl. In some embodiments, R6 and R7 are independently selected at each occurrence from H and C1-6alkyl.

[0391] In some embodiments, each R8 is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R8 is independently selected from H, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R8 is independently selected from H and C1-6alkyl.

[0392] In some embodiments, each R9 is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6 haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R9 is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl. In some embodiments, each R9 is independently selected from C1-6alkyl.

[0393] In some embodiments, each R10 is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3-10cycloalkyl. In some embodiments, each R10 is independently selected from H, C1-6alkyl, and C1-6haloalkyl. In some embodiments, each R10 is independently selected from H and C1-6alkyl.

[0394] In some embodiments, n is 1, 2, 3, or 4. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0395] In some embodiments, m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 6. In some embodiments, m is 7. In some embodiments, m is 8. In some embodiments, m is 9. In some embodiments, m is 10.

[0396] In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.

[0397] In another aspect, provided herein is a compound of Formula IIq:or a pharmaceutically acceptable salt thereof, wherein:

[0399] R1 is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, —NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, and 5- to 10-membered heteroaryl;

[0400] R2 is H and R3 is —CF3; or

[0401] R2 and R3 are taken together to form oxo;

[0402] each R4 is independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, —NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; or

[0403] two R4's are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C3-10 cycloalkyl, and any remaining R4's are independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR9, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, — NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, —NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;

[0404] R5 is selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR9, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, —NR10SO2NR6R7, C1-6alkyl, C1-6 heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;

[0405] R6 and R7 are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6 haloalkyl, and C3-10cycloalkyl;

[0406] each R8 is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;

[0407] each R9 is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10 aryl, and 5- to 10-membered heteroaryl;

[0408] each R10 is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3-10cycloalkyl;

[0409] n is 1, 2, 3, or 4;

[0410] m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; and

[0411] p is 0, 1, 2, or 3.

[0412] In some embodiments, R1 is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, —NR10SO2NR6R7, C1-6alkyl, C1-6 heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, and 5- to 10-membered heteroaryl. In some embodiments, R1 is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, —NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, R1 is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, and —NR10SO2NR6R7. In some embodiments, R1 is selected from C6-10 aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR9, and —C(O)NR6R7.

[0413] In some embodiments, R2 is H and R3 is —CF3. In some embodiments, R2 and R3 are taken together to form oxo.

[0414] In some embodiments, each R4 is independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, —NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R4 is independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, —NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, and C1-6 haloalkyl. In some embodiments, each R4 is independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, and —NR10SO2NR6R7. In some embodiments, each R4 is independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, and —C(O)NR6R7. In some embodiments, each R4 is independently selected from halo. In some embodiments, each R4 is fluoro.

[0415] In some embodiments, two R4's are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4's are independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, —NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, two R4's are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4's are independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, —NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, and C1-6 haloalkyl. In some embodiments, two R4's are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4's are independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, and —NR10SO2NR6R7. In some embodiments, two R4's are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4's are independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, and —C(O)NR6R7.

[0416] In some embodiments, R5 is selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, —NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, R5 is selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, —NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, and C1-6 haloalkyl. In some embodiments, R5 is selected from halo, —NR6R7, —OR8, —C(O)R9, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, and —NR10SO2NR6R7. In some embodiments, R5 is selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR9, and —C(O)NR6R7.

[0417] In some embodiments, R6 and R7 are independently selected at each occurrence from H, C1-6 alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl. In some embodiments, R6 and R7 are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl. In some embodiments, R6 and R7 are independently selected at each occurrence from H and C1-6alkyl.

[0418] In some embodiments, each R8 is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R8 is independently selected from H, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R8 is independently selected from H and C1-6alkyl.

[0419] In some embodiments, each R9 is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6 haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R9 is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl. In some embodiments, each R9 is independently selected from C1-6alkyl.

[0420] In some embodiments, each R10 is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3-10cycloalkyl. In some embodiments, each R10 is independently selected from H, C1-6alkyl, and C1-6haloalkyl. In some embodiments, each R10 is independently selected from H and C1-6alkyl.

[0421] In some embodiments, n is 1, 2, 3, or 4. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0422] In some embodiments, m is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 3. In some embodiments, m is 4. In some embodiments, m is 5. In some embodiments, m is 6. In some embodiments, m is 7. In some embodiments, m is 8. In some embodiments, m is 9. In some embodiments, m is 10.

[0423] In some embodiments, p is 0, 1, 2, or 3. In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, p is 2. In some embodiments, p is 3.

[0424] In another aspect, provided herein is a compound of Formula IIIc:or a pharmaceutically acceptable salt thereof, wherein:

[0426] each X is independently selected from N and CR7;

[0427] Y is selected from O, S, SO2, and C(R8)2;

[0428] R1 is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6 haloalkyl, C3-6cycloalkyl, and 5- to 10-membered heteroaryl;

[0429] R2 is H and R3 is —CF3; or

[0430] R2 and R3 are taken together to form oxo;

[0431] R4 and R5 are independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-6 cycloalkyl; wherein each alkyl, heteroalkyl, haloalkyl, and cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6 haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; or

[0432] R4 and R5 are taken together, along with the nitrogen atom to which they are attached, to form a 3- to 10-membered heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;

[0433] each R6 is independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; or

[0434] two R6's attached to the same carbon atom are taken together to form oxo, and any remaining R6's are independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;

[0435] each R7 and R8 is independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;

[0436] R9 and R10 are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6 haloalkyl, and C3-6cycloalkyl;

[0437] each R11 is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;

[0438] each R12 is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, C6-10 aryl, and 5- to 10-membered heteroaryl;

[0439] each R13 is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3-6cycloalkyl; and

[0440] n is 0, 1, 2, 3, or 4.

[0441] In some embodiments, each X is independently selected from N and CR7. In some embodiments, at least one X is N and the rest are CR7. In some embodiments, at least two X are N and the rest are CR7. In some embodiments, each X is N. In some embodiments, each X is CR7.

[0442] In some embodiments, Y is selected from O, S, SO2, and C(R8)2. In some embodiments, Y is O. In some embodiments, Y is S. In some embodiments, Y is SO2. In some embodiments, Y is C(R8)2.

[0443] In some embodiments, R1 is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6cycloalkyl, and 5- to 10-membered heteroaryl. In some embodiments, R1 is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, R1 is selected from C6-10 aryl and 5- to 10-membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, and —NR13SO2NR9R10. In some embodiments, R1 is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, and —C(O)NR9R10.

[0444] In some embodiments, R2 is H and R3 is —CF3. In some embodiments, R2 and R3 are taken together to form oxo.

[0445] In some embodiments, R4 and R5 are independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-10 cycloalkyl; wherein each alkyl, heteroalkyl, haloalkyl, and cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6 haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, R4 and R5 are independently selected from C3-10cycloalkyl; wherein each cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6 alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, R4 and R5 are independently selected from C3-10cycloalkyl; wherein each cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, R4 and R5 are independently selected from C3-10 cycloalkyl; wherein each cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, and —NR13SO2NR9R10. In some embodiments, R4 and R5 are independently selected from C3-10cycloalkyl; wherein each cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, and —C(O)NR9R10.

[0446] In some embodiments, R4 and R5 are taken together, along with the nitrogen atom to which they are attached, to form a 3- to 10-membered heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, R4 and R5 are taken together, along with the nitrogen atom to which they are attached, to form a 3- to 10-membered heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, R4 and R5 are taken together, along with the nitrogen atom to which they are attached, to form a 3- to 10-membered heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, and —NR13SO2NR9R10. In some embodiments, R4 and R5 are taken together, along with the nitrogen atom to which they are attached, to form a 3- to 10-membered heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, and —C(O)NR9R10.

[0447] In some embodiments, each R6 is independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R6 is independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R6 is independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, and —NR13SO2NR9R10. In some embodiments, each R6 is independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, and —C(O)NR9R10.

[0448] In some embodiments, two R6's attached to the same carbon atom are taken together to form oxo, and any remaining R6's are independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10 -membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, two R6's attached to the same carbon atom are taken together to form oxo, and any remaining R6's are independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, two R6's attached to the same carbon atom are taken together to form oxo, and any remaining R6's are independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, and —NR13SO2NR9R10. In some embodiments, two R6's attached to the same carbon atom are taken together to form oxo, and any remaining R6's are independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, and —C(O)NR9R10.

[0449] In some embodiments, each R7 and R8 is independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-6 cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R7 and R8 is independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R7 and R8 is independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, and —NR13SO2NR9R10. In some embodiments, each R7 and R8 is independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, and —C(O)NR9R10.

[0450] In some embodiments, R9 and R10 are independently selected at each occurrence from H, C1-6 alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl. In some embodiments, R9 and R10 are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, R9 and R10 are independently selected at each occurrence from H and C1-6alkyl.

[0451] In some embodiments, each R11 is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R11 is independently selected from H, C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R11 is independently selected from H and C1-6alkyl.

[0452] In some embodiments, each R12 is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6 haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl. In some embodiments, each R12 is independently selected from C1-6alkyl, C1-6heteroalkyl, and C1-6haloalkyl. In some embodiments, each R12 is independently selected from C1-6alkyl.

[0453] In some embodiments, each R13 is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3-10cycloalkyl. In some embodiments, each R13 is independently selected from H, C1-6alkyl, and C1-6haloalkyl. In some embodiments, each R13 is independently selected from H and C1-6alkyl.

[0454] In some embodiments, n is 0, 1, 2, 3, or 4. In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0455] In another aspect, provided herein is a composition comprising a compound selected from the group consisting of:

[0456] In another aspect, provided herein is a composition comprising a compound selected from the group consisting of: In another aspect, provided herein is a composition comprising a compound selected from the group consisting of:In some cases, the solubility and hPGDH IC50 of the inhibitors are characterized as shown in Tables 1 and 2.TABLE 1Characteristics of PGDH Inhibitors with a 6-5 ring core.hPGDH: IC50Solubility atStructure(uM)pH 7.4 (μM)0.05741400.01951400.02011600.00060.00251.25932.86960.04490.04710.15794.54070.00560.06470.27360.57570.00570.00520.0018340.01220.04660.00271200.0439160.11640.00320.0249330.0015210.01060.1968450.01281500.0493<5.00.0031680.04371600.00641500.00586.90.0005<5.0TABLE 2Characteristics of PGDH Inhibitors with a phenyl core.hPGDH: IC50Solubility at pHStructure(uM)7.4 (μM)0.1350.27720.00852.28381600.0186380.0271290.5933880.00316.3 Provided in Table 3 are analytical data for some of the inhibitors described herein.TABLE 3Analytical data for select inhibitorsMass Spec.Calculated / Mass Spec.1H NMR (DMSO-d6*, 400 MHz)Target NoStructureYield / PurityFound (m / z)(*unless otherwise indicated)MF-PGDH-01510.5% / 98.06%365.13 for C21H20ClN 3O / 366.0 (M + 1)δ 8.69 (s, 1H), 7.86-7.89 (m, 2H), 7.65-7.73 (m, 3H), 7.58-7.61 (m, 1H), 7.48 (dd, J = 1.5, 8.4 Hz, 1H), 3.69 (br s, 2H), 3.37 (br d, J = 8.8 Hz, 1H), 3.26 (br s, 1H), 2.61- 2.68 (m, 2H), 1.65-1.79 (m, 3H), 1.48-1.60 (m, 2H), 1.29-1.41 (m, 1H).MF-PGDH-0168.6% / 98.08%353.13 for C20H20ClN 3O / 354.0 (M + 1)δ 8.69 (s, 1H), 7.87 (t, J = 1.8 Hz, 1H), 7.65-7.75 (m, 4H), 7.57-7.61 (m, 1H), 7.32-7.36 (m, 1H), 3.59 (br t, J = 5.3 Hz, 2H), 3.37 (br s, 2H), 1.75 (br s, 2H), 1.52-1.62 (m, 6H).MF-PGDH-0179.8% / 98.72%337.10 for C19H16ClN 3O / 338.0 (M + 1)δ 8.69-8.69 (m, 1H), 7.86-7.87 (m, 2H), 7.65-7.73 (m, 3H), 7.58- 7.61 (m, 1H), 7.44 (dd, J = 1.5, 8.4 Hz, 1H), 3.97-4.02 (m, 1H), 3.72 (br d, J = 8.3 Hz, 1H), 3.36- 3.42 (m, 2H), 1.56 (br d, J = 1.3 Hz, 2H), 0.62-0.68 (m, 1H), 0.12 (q, J = 4.1 Hz, 1H).MF-PGDH-01813.7% / 97.46%365.13 for C21H20ClN 3O / 366.0 (M + 1)δ 8.68 (s, 1H), 7.86 (t, J = 2.0 Hz, 1H), 7.70-7.73 (m, 2H), 7.64-7.69 (m, 2H), 7.57-7.61 (m, 1H), 7.33 (dd, J = 1.4, 8.4 Hz, 1H), 4.29-4.43 (m, 1H), 3.32-3.42 (m, 1H), 3.17- 3.28 (m, 1H), 2.76-3.00 (m, 1H), 2.04-2.33 (m, 2H), 1.49-1.67 (m, 5H), 1.31-1.45 (m, 1H).MF-PGDH-01916.6% / 92.94%351.11 for C20H18ClN 3O / 352.0 (M + 1)δ 8.72 (s, 1H), 8.03 (s, 1H), 7.88 (t, J = 1.9 Hz, 1H), 7.60-7.74 (m, 5H), 4.35 (br s, 2H), 4.07 (br s, 2H), 2.19 (t, J = 7.6 Hz, 4H), 1.76- 1.83 (m, 2H).MF-PGDH-0234.8% / 98.86%339.11 for C19H18ClN 3O / 340.00 (M + 1)δ 8.70 (s, 1H), 7.88 (s, 1H), 7.75 (m, 1H), 7.63-7.73 (m, 3H), 7.57- 7.61 (m. 1H), 7.35-7.39 (m, 1H), 3.35-3.70 (br s, 4H), 1.45-1.70 (m, 6H).MF-PGDH-0254.6% / 99.70%341.09 for C18H16ClN 3O2 / 342.0 (M + 1)δ 8.70 (s, 1H), 7.86 (t, J = 1.9 Hz, 1H), 7.83 (d, J = 1.0 Hz, 1H), 7.65-7.73 (m, 3H), 7.58-7.61 (m, 1H), 7.41 (dd, J = 1.5, 8.4 Hz, 1H), 3.62 (br s, 5H), 3.55 (br d, J = 9.9 Hz, 3H).MF-PGDH-0268.8% / 98.37%375.09 for C23H28ClFN 4O3 / 376.0 (M + 1)δ 8.70 (s, 1H), 7.86-7.89 (m, 2H), 7.65-7.74 (m, 3H), 7.58-7.61 (m, 1H), 7.43-7.46 (m, 1H), 3.52-3.73 (m, 4H), 2.07 (br d, J = 5.1 Hz, 4H).MF-PGDH-04623.3% / 99.32%325.10 for C18H16ClN 3O / 326.2 (M + 1)δ 8.69 (s, 1H), 7.93 (d, J = 0.9 Hz, 1H), 7.87 (t, J = 1.9 Hz, 1H), 7.65- 7.73 (m, 3H), 7.58-7.61 (m, 1H), 7.51-7.54 (m, 1H), 3.44-3.53 (m, 4H), 1.78-1.93 (m, 4H).MF-PGDH-04723.46% / 99.75%361.08 for C18H14ClF 2N3O / 362.2 (M + 1)δ 8.72 (s, 1H), 7.99 (d, J = 0.98 Hz, 1H), 7.87 (t, J = 1.9 Hz, 1H), 7.65- 7.74 (m, 3H), 7.54-7.62 (m, 2H), 3.90-4.00 (m, 2H), 3.76 (t, J = 7.4 Hz, 2H), 2.39-2.47 (m, 2H).MF-PGDH-04823.2% / 99.56%343.09 for C18H15ClF N3O / 344.2 (M + 1)δ 8.71 (s, 1H), 7.96 (br d, J = 7.58 Hz, 1H), 7.87 (t, J = 1.9 Hz, 1H), 7.64-7.74 (m, 3H), 7.51- 7.62 (m, 2H), 5.22-5.48 (m, 1H), 3.51-3.97 (m, 4H), 2.03-2.26 (m, 2H).MF-PGDH-04957% / 99.51%359.06 for C18H15Cl2 N3O / 360.1 (M + 1)δ 8.71 (s, 1H), 7.95 (br d, J = 13.6 Hz, 1H), 7.87 (t, J = 1.9 Hz, 1H), 7.65-7.74 (m, 3H), 7.58-7.62 (m, 1H), 7.51-7.57 (m, 1H), 4.72- 4.87 (m, 1H), 3.91-4.09 (m, 1H), 3.74-3.81 (m, 1H), 3.52-3.67 (m, 2H), 2.37-2.45 (m, 1H), 2.08-2.20 (m, 1H).MF-PGDH-05064% / 99.53%341.09 for C18H16ClN 3O2 / 342.2 (M + 1)δ 8.70 (s, 1H), 7.86-7.92 (m, 2H), 7.66-7.73 (m, 3H), 7.58-7.61 (m, 1H), 7.51-7.54 (m, 1H), 4.91-5.03 (m, 1H), 4.22-4.37 (m, 1H), 3.41- 3.67 (m, 4H), 1.78-1.99 (m, 2H).MF-PGDH-05211.34% / 99.89%355.11 for C19H18ClN 3O2 / 356.2 (M + 1)δ 8.69 (s, 1H), 7.87 (t, J = 1.9 Hz, 1H), 7.77 (d, J = 1.0 Hz, 1H), 7.64- 7.73 (m, 3H), 7.58-7.61 (m, 1H), 7.37 (dd, J = 1.5, 8.31 Hz, 1H), 4.77 (d, J = 4.0 Hz, 1H), 3.87-4.1 (m, 1H), 3.75 (dt, J = 4.2, 8.16 Hz, 1H), 3.21 (brs, 2H), 1.70-1.83 (m, 2H), 1.32-1.44 (m, 2H).MF-PGDH-06311.09% / 99.48%311.08 for C17H14ClN 3O / 312.0 (M + 1)δ 8.70 (s, 1H), 8.50 (br d, J = 4.0 Hz, 1H), 8.30 (d, J = 0.9 Hz, 1H), 7.85-7.89 (m, 2H), 7.64- 7.74 (m, 3H), 7.57-7.62 (m, 1H), 2.85-2.93 (m, 1H), 0.58- 0.73 (m, 4H).MF-PGDH-06520.22% / 99.07%347.08 for C20H14ClN 3O / 348.1 (M + 1)δ 10.31 (s, 1H), 8.76 (s, 1H), 8.51 (d, J = 1.3 Hz, 1H), 7.98-8.02 (m, 1H), 7.89-7.91 (m, 1H), 7.84 (d, J = 7.6 Hz, 2H), 7.73-7.78 (m, 2H), 7.67-7.71 (m, 1H), 7.60-7.63 (m, 1H), 7.34-7.39 (m, 2H), 7.08-7.12 (m, 1H).MF-PGDH-1037.58% / 99.74%299.08 for C16H14ClN 3O / 300.2 (M + 1)δ 8.69 (s, 1H), 7.87 (t, J = 1.9 Hz, 1H), 7.82 (d, J = 0.9 Hz, 1H), 7.65- 7.73 (m, 3H), 7.58-7.61 (m, 1H), 7.40 (dd, J = 1.5, 8.4 Hz, 1H), 3.00 (br s, 6H).MF-PGDH-10423.91% / 98.08%311.08 for C17H14ClN 3O / 312.2 (M + 1)δ 8.71 (s, 1H), 8.00 (d, J = 0.8 Hz, 1H), 7.87 (t, J = 1.9 Hz, 1H), 7.58- 7.73 (m, 5H), 4.36 (br t, J = 6.7 Hz, 2H), 4.08 (br t, J = 6.8 Hz, 2H), 2.24-2.31 (m, 2H).MF-PGDH-10511.5% / 99.69%339.11 for C19H18ClN 3O / 340.0 (M + 1)δ 8.71 (s, 1H), 8.02 (s, 1H), 7.87 (t, J = 1.8 Hz, 1H), 7.63-7.73 (m, 4H), 7.58-7.61 (m, 1H), 4.05 (s, 2H), 3.76 (s, 2H), 1.26 (s, 6H).MF-PGDH-10657% / 97.93%329.07 for C17H13ClF N3O / 330.1 (M + 1)δ 8.73 (s, 1H), 8.05 (s, 1H), 7.87 (t, J = 1.8 Hz, 1H), 7.59-7.73 (m, 5H), 5.36-5.56 (m, 1H), 4.33-4.74 (m, 3H), 4.03-4.23 (m, 1H).MF-PGDH-1079.8% / 99.89%345.04 for C17H13Cl2 N3O / 345.9 (M + 1)δ 8.73 (s, 1H), 8.03 (s, 1H), 7.87- 7.88 (m, 1H), 7.64-7.74 (m, 4H), 7.59-7.62 (m, 1H), 4.88 (dd, J = 4.0, 6.5 Hz, 2H), 4.61-4.69 (m, 1H), 4.43-4.52 (m, 1H), 4.06-4.18 (m, 1H).MF-PGDH-05157% / 98.33%340.11 for C18H17ClN 4O / 341.2 (M + 1)δ 8.70 (s, 1H), 7.85-7.96 (m, 2H), 7.65-7.73 (m, 3H), 7.49-7.61 (m, 2H), 3.58-3.70 (m, 3H), 3.40-3.55 (m, 3H), 3.15-3.27 (m, 1H), 1.97- 2.07 (m, 1H), 1.66-1.75 (m, 1H).MF-PGDH-0646.84% / 99.68%325.10 for C18H16ClN 3O / 326.2 (M + 1)δ 8.68 (s, 1H), 7.94 (s, 1H), 7.88 (t, J = 2.0 Hz, 1H), 7.71-7.74 (m, 1H), 7.64-7.69 (m, 2H), 7.57-7.61 (m, 1H), 7.49-7.52 (m, 1H), 3.00 (s, 4H), 0.40-0.56 (m, 4H).MF-PGDH-0903.85% / 91.38%339.08 for C18H14ClN 3O2 / 340.2 (M + 1)CDCl3 δ 8.19-8.19 (m, 1H), 8.04 (s, 1H), 7.58-7.61 (m, 2H), 7.55 (dd, J = 2.7, 4.9 Hz, 2H), 7.49-7.52 (m, 1H), 7.42-7.45 (m, 1H), 4.05- 4.16 (br s, 2H), 3.76-3.79 (m, 1H), 3.62-3.65 (m, 1H), 2.67 (brt, J = 7.8 Hz, 2H).MF-PGDH-10269.51% / 99.99%271.05 for C14H10ClN 3O / 272.1 (M + 1)δ 8.70 (s, 1H), 8.36 (s, 1H), 8.05 (br s, 1H), 7.91-7.93 (m, 1H), 7.87 (s, 1H), 7.68-7.73 (m, 3H), 7.66-7.67 (m, 1H), 7.59 (brd, J = 7.7 Hz, 1H).MF-PGDH-0277.55% / 99.90%411.13 for C22H22ClN 3O3 / 412.0 (M + 1)δ 7.88-7.89 (m, 1H), 7.79 (t, J = 1.77 Hz, 1H), 7.60-7.69 (m, 2H), 7.54-7.58 (m, 1H), 7.42 (dd, J = 1.47, 8.56 Hz, 1H), 7.24 (dd, J = 0.61, 8.44 Hz, 1H), 4.25 (q, J = 7.09 Hz, 2H), 3.48-3.68 (m, 2H), 3.33-3.47 (m, 2H), 1.45-1.67 (m, 6H), 1.18 (t, J = 7.09 Hz, 4H).MF-PGDH-03013.7% / 94.95%425.15 for 23H24ClN3 O3 / 426.0 (M + 1)δ 7.72-7.74 (m, 1H), 7.66-7.69 (m, 3H), 7.53-7.56 (m, 1H), 7.21- 7.29 (m, 2H), 4.05 (s, 2H), 3.93- 3.99 (m, 2H), 3.37-3.68 (m, 4H), 1.60-1.64 (m, 2H), 1.45-1.58 (m, 4H), 1.05 (t, J = 7.09 Hz, 3H).MF-PGDH-0912.9% / 98.92%353.13 for C20H20ClN 3O / 354.2 (M + 1)δ 7.78-7.79 (m, 1H), 7.65-7.70 (m, 2H), 7.56-7.62 (m, 2H), 7.17- 7.23 (m, 2H), 3.41-3.65 (m, 4H), 2.46 (s, 3H), 1.59-1.64 (m, 2H), 1.46-1.57 (m, 4H).MF-PGDH-0337.1% / 97.95%425.15 for C24H26ClN 3O3 / 426.0 (M + 1)δ 7.77-7.79 (m, 1H), 7.67-7.73 (m, 2H), 7.63-7.66 (m, 1H), 7.56- 7.61 (m, 1H), 7.16-7.24 (m, 2H), 3.57 (s, 3H), 3.38-3.51 (m, 2H), 2.89-3.01 (m, 4H), 1.46-1.66 (m, 6H).MF-PGDH-0343.6% / 95.15%411.13 for C22H22ClN 3O3 / 426.0 (M + 1)δ 7.77-7.78 (m, 1H), 7.68-7.71 (m, 2H), 7.63-7.64 (m, 1H), 7.56- 7.60 (m, 1H), 7.16-7.25 (m, 2H), 6.97-7.15 (m, 2H), 3.39-3.56 (m, 3H), 2.92-2.96 (m, 2H), 2.80-2.85 (m, 2H), 1.62 (br d, J = 3.55 Hz, 2H), 1.51 (br s, 4H).MF-PGDH-03517.3% / 97.93%410.15 for C22H23ClN 4O2 / 411.3 (M + 1)δ 7.79-7.80 (m, 1H), 7.67-7.70 (m, 2H), 7.57-7.63 (m, 2H), 7.40 (br s, 1H), 7.15-7.23 (m, 2H), 6.80 (br s, 1H), 3.34-3.61 (m, 4H), 2.89-2.94 (m, 2H), 2.66-2.70 (m, 2H), 1.47-1.65 (m, 6H).MF-PGDH-00813.5% / 96.97%335.16 for C20H21N3 O2 / 336.1 (M + 1)δ 8.55 (s, 1H), 7.74 (s, 1H), 7.60 (d, J = 8.9 Hz, 2H), 7.54 (d, J = 8.3 Hz, 1H), 7.32 (dd, J = 8.3, 1.5 Hz, 1H), 7.18 (d, J = 9.0 Hz, 2H), 3.85 (s, 3H), 3.52-3.40 (m, 4H), 1.62-1.51 (m, 6 H).MF-PGDH-00918.2% / 99.52%353.15 for C20H20FN3 O2 / 354.0 (M + 1)δ 8.56 (s, 1H), 7.80 (d, J = 0.98 Hz, 1H), 7.54-7.63 (m, 3H), 7.36 (dd, J = 1.47, 8.4 Hz, 1H), 7.16-7.20 (m, 2H), 4.83-5.01 (m, 1H), 3.85 (s, 3H), 3.43-3.70 (m, 4H), 1.84- 2.00 (m, 2H), 1.74 (br d, J = 2.9 Hz, 2H).MF-PGDH-02114.6% / 99.43%375.19 for C23H25N3 O22 / 376.0 (M + 1)δ 7.50-7.54 (m, 3H), 7.14-7.22 (m, 3H), 7.07-7.10 (m, 1H), 3.87 (s, 3H), 3.35-3.55 (m, 3H), 1.78- 1.86 (m, 1H), 1.45-1.65 (m, 6H), 1.21-1.28 (m, 1H), 1.10-1.14 (m, 2H), 0.98-1.03 (m, 2H).MF-PGDH-02251% / 99.72%336.16 for C19H20N4 O2 / 337.1 (M + 1)δ 8.92 (s, 1H), 8.36 (d, J = 2.93 Hz, 1H), 8.17 (d, J = 8.44 Hz, 1H), 7.91 (d, J = 8.93 Hz, 1H), 7.75- 7.70 (m, 2H), 7.37 (dd, J = 1.53, 8.38 Hz, 1H), 3.92 (s, 3H), 3.56- 3.37 (m, 4H), 1.63-1.53 (m, 6H).MF-PGDH-02445.3% / 99.10%369.12 for C20H20ClN 3O2 / 370.2 (M + 1)δ 8.68 (s, 1H), 7.76 (s, 1H), 7.73 (d, J = 8.3 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 2.4 Hz, 1H), 7.35 (dd, J = 8.3, 1.5 Hz, 1H), 7.32-7.29 (dd, J = 8.4, 2.3 Hz, 1H), 3.97 (s, 3H), 3.50-3.46 (m, 4H), 1.63-1.53 (m, 6 H)MF-PGDH-06223.6% / 97.72%349.14 for C20H19N3 O3 / 350.0 (M + 1)δ 8.54 (s, 1H), 7.73 (s, 1H), 7.57 (d, J = 8.3 Hz, 1H), 7.35-7.31 (m, 2H), 7.18-7.06 (m, 2H), 6.17 (s, 2H), 3.53-3.41 (m, 4H), 1.63-1.52 (m, 6 H).MF-DH-14114.5% / 99.11%325.13 for C19H19FN4 O2 / 326.1 (M + 1)δ 9.12 (s, 1H), 9.03 (d, J = 5.8 Hz, 1H), 8.94 (d, J = 5.77 Hz, 1H), 8.54-8.52 (m, 2H), 8.24 (d, J = 1.92 Hz, 1H), 6.94 (d, J = 3.84 Hz, 1H), 5.02-4.97 (m, 1H), 3.93 (s, 3H), 3.60 (m, 4H), 1.99-1.75 (m, 6H).MF-PGDH-06134.8% / 98.88%355.11 for C19H18ClN 3O2 / 356.2 (M + 1)δ 10.83 (br s, 1H), 8.62 (s, 1H), 7.75 (d, J = 0.9 Hz, 1H), 7.64 (dd, J = 0.5, 8.3 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.36 (dd, J = 8.4, 1.5 Hz, 1H), 7.23 (d, J = 2.6 Hz, 1H), 7.14 (dd, J = 8.4, 2.4 Hz, 1H), 3.54-3.42 (m, 4H), 3.32 (s, 3H) 1.63-1.53 (m, 6 H).MF-PGDH-01421.4% / 99.15%339.11 for C19H18ClN 3O / 340.0 (M + 1)δ 8.39 (s, 1H), 8.18-8.07 (m, 3H), 7.94-7.87 (m, 1H), 7.62- 7.55 (m, 1H), 7.46-7.38 (m, 1H), 6.82 (s, 1H), 3.67-3.38 (m, 4H), 1.68-1.43 (m, 6H)MF-PGDH-06721.0% / 99.65%306.15 for C18H18N4 O / 307.3 (M + 1)δ 8.85 (d, J = 8.3 Hz, 1H), 8.55 (dd, J = 1.0, 4.8 Hz, 1H), 8.47 (d, J = 3.8 Hz, 1H), 8.43 (d, J = 2.0 Hz, 1H), 8.16 (d, J = 2.1 Hz, 1H), 8.06 (ddd, J = 2.0, 7.4, 8.3 Hz, 1H), 7.36 (ddd, J = 0.8, 4.9, 7.3 Hz, 1H), 6.84 (d, J = 3.9 Hz, 1H), 3.73-3.37 (m, 4H), 1.71-1.42 (m, 6H)MF-PGDH-06837.5% / 99.00%306.15 for C18H18N4 O / 307.2 (M + 1)δ 9.14 (d, J = 2.4 Hz, 1H), 8.58 (dd, J = 1.6, 4.8 Hz, 1H), 8.38 (dd, J = 1.6, 2.8 Hz, 1H), 8.36 (t, J = 2.0 Hz, 1H), 8.15-8.13 (m, 2H), 7.63-7.60 (m, 1H), 6.85 (d, J = 3.6 Hz, 1H), 3.59-3.42 (m, 4H), 1.68-1.43 (m, 6H)MF-PGDH-0692.3% / 97.98%307.14 for C17H17N5 O / 308.2 (M + 1)δ 9.12 (d, J = 1.0 Hz, 1H), 9.03 (dd, J = 1.3, 5.7 Hz, 1H), 8.94 (d, J = 5.7 Hz, 1H), 8.53 (d, J = 4.0 Hz, 1H), 8.48 (d, J = 2.0 Hz, 1H), 8.19 (d, J = 2.0 Hz, 1H), 6.93 (d, J = 4.0 Hz, 1H), 3.72- 3.35 (m, 4H), 1.71-1.40 (m, 6H)MF-PGDH-07015.2% / 99.91%307.14 for C17H17N5 O / 308.2 (M + 1)δ 9.47 (s, 2H), 9.18 (s, 1H), 8.40 (d, J = 2.0 Hz, 1H), 8.23 (d, J = 3.7 Hz, 1H), 8.18 (d, J = 2.1 Hz, 1H), 6.91 (d, J = 3.8 Hz, 1H), 3.79-3.37 (m, 4H), 1.74-1.40 (m, 6H)MF-PGDH-07119.3 % / 99.50%307.14 for C17H17N5 O / 308.2 (M + 1)δ 10.10 (d, J = 1.3 Hz, 1H), 8.69- 8.58 (m, 2H), 8.48 (d, J = 2.1 Hz, 1H), 8.40 (d, J = 3.8 Hz, 1H), 8.19 (d, J = 2.0 Hz, 1H), 6.93 (d, J = 3.8 Hz, 1H), 3.75-3.39 (m, 4H), 1.75-1.43 (m, 6H)MF-PGDH-07331.5% / 95.38%323.17 for C18H21N5 O / 324.1 (M + 1)δ 8.37 (brs, 1H), 8.10 (br s, 2H), 7.93-7.59 (m, 2H), 6.73 (br s, 1H), 4.11 (q, J = 7.1 Hz, 2H), 3.74-3.35 (m, 4H), 1.71-1.48 (m, 6H), 1.42 (t, J = 7.2 Hz, 3H)MF-PGDH-07430.4% / 99.72%312.10 for C16H16N4 OS / 313.0 (M + 1)δ 9.22 (d, J = 1.8 Hz, 1H), 8.44 (d, J = 1.1 Hz, 1H), 8.36 (d, J = 1.8 Hz, 1H), 8.29 (d, J = 3.7 Hz, 1H), 8.16 (d, J = 1.5 Hz, 1H), 6.81 (d, J = 3.7 Hz, 1H), 3.76- 3.36 (m, 4H), 1.78-1.36 (m, 6H)MF-PGDH-07526.8% / 99.41%295.14 for C16H17N5 O / 296.0 (M + 1)δ 13.34-12.77 (m, 1H), 8.42 (s, 1H), 8.37 (d, J = 2.0 Hz, 1H), 8.14 (s, 1H), 8.11 (d, J = 2.0 Hz, 1H), 7.98 (d, J = 3.4 Hz, 1H), 6.76 (d, J = 3.5 Hz, 1H), 3.69- 3.41 (m, 4H), 1.73-1.46 (m, 6H)MF-PGDH-07634.5% / 98.55%309.16 for C17H19N5 O / 310.1 (M + 1)δ 8.43 (s, 1H), 8.35 (d, J = 2.1 Hz, 1H), 8.09 (d, J = 2.1 Hz, 1H), 8.03 (d, J = 0.6 Hz, 1H), 7.96 (d, J = 3.5 Hz, 1H), 6.74 (d, J = 3.5 Hz, 1H), 3.93 (s, 3H), 3.69-3.37 (m, 4H), 1.77-1.39 (m, 6H)MF-DH-12330.9% / 99.52%325.13 for C17H16FN5 O / 326.1 (M + 1)δ 10.11 (d, J = 1.3 Hz, 1H), 8.68- 8.61 (m, 2H), 8.54 (d, J = 2.0 Hz, 1H), 8.43 (d, J = 3.9 Hz, 1H), 8.26 (d, J = 2.1 Hz, 1H), 6.95 (d, J = 3.8 Hz, 1H), 5.08-4.84 (m, 1H), 3.85-3.54 (m, 4H), 2.07- 1.73 (m, 4H)MF-DH-12848.2% / 99.68%415.20 for C24H25N5 O2 / 416.1 (M + 1)δ 8.36 (br s, 1H), 8.17-8.04 (m, 2H), 7.83 (brd, J = 16.0 Hz, 2H), 7.35 (d, J = 8.6 Hz, 2H), 6.96 (d, J = 8.7 Hz, 2H), 6.74 (br s, 1H), 5.25 (s, 2H), 3.75 (s, 3H), 3.66- 3.37 (m, 4H), 1.79-1.43 (m, 6H)MF-DH-12945.8% / 99.17%415.20 for C24H25N5 O2 / 416.1 (M + 1)δ 8.52 (d, J = 0.6 Hz, 1H), 8.34 (d, J = 2.0 Hz, 1H), 8.08 (dd, J = 1.4, 3.2 Hz, 2H), 7.98 (d, J = 3.7 Hz, 1H), 7.29 (d, J = 8.7 Hz, 2H), 6.92 (d, J = 8.7 Hz, 2H), 6.74 (d, J = 3.7 Hz, 1H), 5.33 (s, 2H), 3.73 (s, 3H), 3.66-3.35 (m, 4H), 1.72-1.43 (m, 6H) MF-DH-13148.2% / 99.11%325.13 for C17H16FN5 O / 326.1 (M + 1)δ 9.12 (s, 1H), 9.03 (d, J = 5.8 Hz, 1H), 8.94 (d, J = 5.8 Hz, 1H), 8.59-8.49 (m, 2H), 8.24 (d, J = 1.9 Hz, 1H), 6.94 (d, J = 3.8 Hz, 1H), 5.05-4.81 (m, 1H), 3.83- 3.36 (m, 4H), 2.04-1.64 (m, 4H)MF-13211.2% / 98.86%359.09 for C17H15ClF N5O / 360.0 (M + 1)δ 9.14 (s, 1H), 8.96 (s, 2H), 8.69 (s, 1H), 8.62 (d, J = 1.8 Hz, 1H), 8.21 (d, J = 1.8 Hz, 1H), 5.13- 4.80 (m, 1H), 3.88-3.43 (m, 4H), 2.05-1.65 (m, 4H)MF-1332.02% / 92.41%340.13 for C18H17FN4 O2 / 341.0 (M + 1)CDCl3 δ 8.42 (s, 1H), 8.21 (br s, 1H), 8.11 (brd, J = 1.2 Hz, 2H), 7.46 (d, J = 3.5 Hz, 1H), 6.96 (br d, J = 9.4 Hz, 1H), 6.75 (d, J = 3.5 Hz, 1H), 5.72-5.37 (m, 1H), 5.06-4.83 (m, 1H), 4.15-3.41 (m, 4H), 2.20-1.72 (m, 4H)MF-13419.7% / 99.09%324.14 for C18H17FN4 O / 325.0 (M + 1)δ 9.15 (brs, 1H), 8.59 (br d, J = 3.7 Hz, 1H), 8.46-8.34 (m, 2H), 8.20 (d, J = 2.0 Hz, 1H), 8.15 (d, J = 3.7 Hz, 1H), 7.62 (dd, J = 4.7, 8.3 Hz, 1H), 6.86 (d, J = 3.8 Hz, 1H), 5.11-4.80 (m, 1H), 3.79- 3.39 (m, 4H), 2.09-1.64 (m, 4H)MF-1355.4% / 98.86%358.10 for C18H16ClF N4O / 359.0 (M + 1)δ 9.12 (d, J = 2.4 Hz, 1H), 8.61 (dd, J = 1.3, 4.8 Hz, 1H), 8.49 (d, J = 1.8 Hz, 1H), 8.43 (s, 1H), 8.38-8.29 (m, 1H), 8.16 (d, J = 2.0 Hz, 1H), 7.63 (dd, J = 4.8, 8.3 Hz, 1H), 5.15-4.76 (m, 1H), 3.88-3.41 (m, 4H), 2.09-1.62 (m, 4H)MF-13912.2% / 99.18%327.15 for C17H18FN5 O / 328.2 (M + 1)δ 8.43 (s, 1H), 8.39 (d, J = 2.0 Hz, 1H), 8.14 (d, J = 2.1 Hz, 1H), 8.03 (d, J = 0.7 Hz, 1H), 7.97 (d, J = 3.7 Hz, 1H), 6.75 (d, J = 3.5 Hz, 1H), 5.08-4.76 (m, 1H), 3.93 (s, 3H), 3.73-3.43 (m, 4H), 2.03-1.67 (m, 4H)MF-1402.6% / 99.84%361.11 for C17H17ClF N5O / 362.0 (M + 1)δ 8.48 (d, J = 1.8 Hz, 1H), 8.41 (s, 1H), 8.26 (s, 1H), 8.10 (d, J = 2.0 Hz, 1H), 8.01 (s, 1H), 5.07- 4.76 (m, 1H), 3.93 (s, 3H), 3.79- 3.38 (m, 4H), 2.10-1.66 (m, 4H)MF-14536.5% / 98.03%359.09 for C17H15ClF N5O / 360.0 (M + 1)δ 9.43 (s, 2H), 9.21 (s, 1H), 8.58- 8.44 (m, 2H), 8.19 (d, J = 2.0 Hz, 1H), 5.15-4.74 (m, 1H), 3.85- 3.39 (m, 4H), 2.10-1.59 (m, 4H)MF-1577.4% / 99.53%354.15 for C19H19FN4 O2 / 355.1 (M + 1)δ 8.60 (d, J = 2.6 Hz, 1H), 8.36 (d, J = 2.0 Hz, 1H), 8.27-8.13 (m, 2H), 8.00 (d, J = 3.7 Hz, 1H), 7.03 (d, J = 8.8 Hz, 1H), 6.81 (d, J = 3.7 Hz, 1H), 5.10-4.77 (m, 1H), 3.93 (s, 3H), 3.78-3.44 (m, 4H), 2.05-1.68 (m, 4H)MF-PGDH-02013.7% / 99.94%340.11 for C18H17ClN 4O / 341.0 (M + 1)δ 9.11 (s, 1H), 8.51 (d, 1H), 8.30 (d, 1H), 8.20-8.22 (m, 1H), 8.01- 8.03 (m, 1H), 7.70-7.72 (m, 1H), 7.57-7.59 (m, 1H), 3.54-3.67 (m, 2H), 3.34-3.42 (m, 2H), 1.48-1.68 (m, 6H).MF-PGDH-07714.8% / 99.66%336.16 for C19H20N4 O2 / 337.2 (M + 1)δ 8.89 (s, 1H), 8.43 (d, J = 1.83 Hz, 1H), 8.20 (d, J = 1.96 Hz, 1H), 7.78-7.82 (m, 2H), 7.15-7.19 (m, 2H), 3.84 (s, 3H), 3.54-3.68 (m, 2H), 3.34-3.45 (m, 2H), 1.49-1.67 (m, 6H).MF-PGDH-07815% / 99.73%354.15 for C19H19FN4 O2 / 355.2 (M + 1)δ 8.90 (s, 1H), 8.47-8.48 (d, J = 1.83 Hz, 1H), 8.25-8.26 (d, J = 1.96 Hz, 1H), 7.79-7.81 (m, 2H), 7.13-7.15 (m, 2H), 4.82-5.01 (m, 1H), 3.84-3.85 (s, 3H), 3.52- 3.80 (m, 4H), 1.83-2.01 (m, 2H), 1.71-1.82 (m, 2H).MF-PGDH-0795.5% / 98.59%372.14 for C19H18F2N 4O2 / 373.2 (M + 1)δ 8.90 (s, 1H), 8.50-8.51 (d, J = 1.83 Hz, 1H), 8.30-8.31 (d, J = 1.96 Hz, 1H), 7.79-7.81 (m, 2H), 7.16-7.18 (m, 2H), 3.84-3.85 (s, 3H), 3.55-3.70 (m, 4H), 2.03- 2.12 (m, 4H).MF-DH-13813.1% / 99.72%326.12 for C17H15FN4 O2 / 327.0 (M + 1)δ 8.92 (s, 1H), 8.70 (d, J = 1.92 Hz, 1H), 8.42 (d, J = 1.92 Hz, 1H), 7.78-7.81 (m, 2H), 7.17 (d, J = 8.97 Hz, 2H), 5.38-5.55 (m, 1H), 4.41-4.71 (m, 3H), 4.09-4.19 (m, 1H), 3.84 (s, 3H).MF-DH-1153.96% / 98.04%369.16 for C19H20FN5 O2 / 370.1 (M + 1)δ 7.78 (d, J = 1.83 Hz, 1H), 7.41 (d, J = 1.83 Hz, 1H), 7.31-7.34 (m, 2H), 7.06 (d, J = 8.93 Hz, 2H), 6.64 (s, 2H), 4.75-4.94 (m, 1H), 3.77 (s, 3H), 3.51 (br d, J = 0.86 Hz, 4H), 1.79-1.88 (m, 2H), 1.67 (br d, J = 2.20 Hz, 2H).MF-DH-1162.12% / 99.12%411.17 for C21H22FN5 O3 / 410.1 (M-1)δ 10.49-10.64 (m, 1H), 8.21-8.23 (m, 1H), 8.00 (br s, 1H), 7.32- 7.34 (m, 2H), 7.02-7.05 (m, 2H), 4.77-4.94 (m, 1H), 3.77 (s, 3H), 3.48-3.62 (m, 4H), 1.82-1.94 (m, 7H).MF-PGDH-0362.05% / 99.77%373.07 for C19H20BrN O2 / 375.9 (M +3)δ 7.60 (dd, J = 1.53, 7.89 Hz, 1H), 7.53 (d, J = 8.07 Hz, 2H), 7.36- 7.42 (m, 2H), 7.32-7.35 (m, 1H), 7.21 (dd, J = 1.22, 8.31 Hz, 1H), 6.91 (dt, J = 1.28, 7.61 Hz, 1H), 5.25 (s, 2H), 3.57 (br s, 2H), 3.27 (br s, 2H), 1.39-1.65 (m, 6H).MF-PGDH-0372.1% / 99%329.12 for C19H20ClN O2 / 330.1 (M + 1)δ 7.52 (d, J = 8.1 Hz, 2H), 7.47- 7.38 (m, 3H), 7.33-7.22 (m, 2H), 6.97 (dt, J = 1.5, 7.6 Hz, 1H), 5.25 (s, 2H), 3.57 (brs, 2H), 3.22-3.30 (m, 2H), 1.65-1.41 (m, 6H).MF-PGDH-0382.1% / 99.95%359.13 for C20H22ClN O3 / 360.0 (M + 1)δ 7.40-7.53 (m, 2H), 7.29 (dd, J = 1.53, 7.40 Hz, 1H), 7.18-7.26 (m, 1H), 7.03 (d, J = 1.10 Hz, 1H), 6.95-7.00 (m, 2H), 5.17 (s, 2H), 3.86 (s, 3H), 3.48-3.66 (m, 2H), 3.19-3.30 (m, 2H), 1.39-1.66 (m, 6H).MF-PGDH-0391.4% / 98.03%345.10 for C19H20ClN OS / 346.0 (M + 1)δ 7.69-7.78 (m, 3H), 7.46-7.50 (m, 1H), 7.22-7.28 (m, 4H), 4.89 (s, 2H), 3.48-3.58 (m, 2H), 3.08- 3.17 (m, 2H), 1.39-1.62 (m, 6H).MF-PGDH-0409.6% / 99.83%377.09 for C19H20ClN O3 / 378.0 (M + 1)δ 7.69-7.78 (m, 3H), 7.45-7.51 (m, 1H), 7.25 (d, J = 1.34 Hz, 4H), 4.89 (s, 2H), 3.54 (brs, 2H), 3.12 (brs, 2H), 1.56-1.63 (m, 2H), 1.34-1.55 (m, 4H).MF-PGDH-04568% / 99.84%361.09 for C19H20ClN O2S / 362.0 (M + 1)δ 7.51-7.60 (m, 2H), 7.40-7.45 (m, 1H), 7.29-7.33 (m, 1H), 7.19- 7.22 (m, 2H), 7.02-7.05 (m, 2H), 4.39-4.45 (m, 1H), 4.17-4.21 (m, 1H), 3.47-3.61 (m, 2H), 3.12-3.20 (m, 2H), 1.57-1.65 (m, 2H), 1.38- 1.56 (m, 4H).MF-PGDH-03830.37% / 99.95%359.13 for C20H22ClN O3 / 360.0 (M + 1)δ 7.40-7.53 (m, 2H), 7.29 (dd, J = 1.53, 7.40 Hz, 1H), 7.18-7.26 (m, 1H), 7.03 (d, J = 1.10 Hz, 1H), 6.95-7.00 (m, 2H), 5.17 (s, 2H), 3.86 (s, 3H), 3.48-3.66 (m, 2H), 3.19-3.30 (m, 2H), 1.39-1.66 (m, 6H).MF-DH-11814.6% / 99.53%377.12 for C20H21 ClF NO3 / 378.0 (M + 1)δ 7.43-7.51 (m, 2H), 7.31 (dt, J = 1.59, 7.83 Hz, 1H), 7.18-7.26 (m, 1H), 7.08 (d, J = 1.10 Hz, 1H), 6.95-7.03 (m, 2H), 5.17 (s, 2H), 4.82-5.01 (m, 1H), 3.86 (s, 4H), 3.34-3.76 (m, 4H), 1.62-2.02 (m, 4H).MF-DH-12161.4% / 99.67%348.10 for C18H18ClF N2O2 / 349.0 (M + 1)δ 8.67-8.71 (m, 1H), 8.01 (dd, J = 2.02, 8.01 Hz, 1H), 7.64 (d, J = 7.95 Hz, 1H), 7.46 (dd, J = 1.47, 7.82 Hz, 1H), 7.26-7.36 (m, 2H), 7.00 (dt, J = 1.59, 7.52 Hz, 1H), 5.31 (s, 2H), 4.83-5.02 (m, 1H), 3.70 (brt, J = 5.50 Hz, 2H), 3.43-3.55 (m, 1H), 3.33-3.40 (m, 1H), 1.64-2.03 (m, 4H).MF-PGDH-09512.4% / 99.23%372.18 for C24H24N2 O2 / 373.1 (M + 1)δ 8.65-8.68 (m, 1H), 7.88-7.92 (m, 1H), 7.77-7.82 (m, 1H), 7.71- 7.74 (m, 1H), 7.47 (d, J = 8.19 Hz, 2H), 7.30-7.42 (m, 4H), 7.21-7.25 (m, 1H), 7.06-7.11 (m, 1H), 5.24 (s, 2H), 3.52-3.62 (m, 2H), 3.20- 3.30 (m, 2H), 1.58-1.64 (m, 2H), 1.41-1.56 (m, 4H).MF-PGDH-0962.05% / 99.19%378.14 for C22H23N3 O2 / 379.0 (M + 1)δ 11.63-12.41 (m, 1H), 8.04 (brd, J = 7.09 Hz, 1H), 7.71 (s, 1H), 7.56 (d, J = 8.07 Hz, 2H), 7.36-7.48 (m, 3H), 7.11-7.20 (m, 2H), 6.99 (t, J = 7.21 Hz, 1H), 5.28 (s, 2H), 3.57 (br d, J = 2.32 Hz, 2H), 3.43-3.52 (m, 2H), 1.43-1.65 (m, 6H).MF-PGDH-09730.9% / 99.72%326.12 for C22H22N2 O2S / 327.0 (M + 1)δ 9.06 (s, 1H), 8.38 (s, 1H), 7.80 (br d, J = 7.34 Hz, 1H), 7.53-7.57 (m, 2H), 7.34-7.42 (m, 3H), 7.26- 7.29 (m, 1H), 7.07 (t, J = 7.34 Hz, 1H), 5.32 (s, 2H), 3.53-3.62 (m, 2H), 3.20-3.34 (m, 2H), 1.43-1.65 (m, 6H).MF-PGDH-0413.53% / 98.91%338.16 for C20H22N2 O3 / 339.1 (M + 1)δ 10.28 (s, 1H), 7.79 (d, J = 8.56 Hz, 2H), 7.61 (dd, J = 1.71, 7.58 Hz, 1H), 7.51 (ddd, J = 1.83, 7.40, 8.38 Hz, 1H), 7.35 (d, J = 8.56 Hz, 2H), 7.18 (d, J = 8.19 Hz, 1H), 7.07 (dt, J = 0.86, 7.46 Hz, 1H), 3.89 (s, 3H), 3.48-3.63 (m, 2H), 3.37-3.47 (m, 2H), 1.61 (brd, J = 4.16 Hz, 2H), 1.51 (br s, 4H).MF-PGDH-04216.71% / 99.67%352.18 for C21H24N2 O3 / 353.1 (M + 1)δ 7.04-7.27 (m, 6H), 6.67-6.89 (m, 2H), 3.42-3.59 (m, 5H), 3.31 (br s, 3H), 2.99-3.12 (m, 2H), 1.31-1.57 (m, 6H).MF-PGDH-0874.77% / 92.51%374.14 for C20H20F2N 2O3 / 375.0 (M + 1)δ 10.30 (s, 1H), 7.81 (d, J = 8.56 Hz, 2H), 7.61 (dd, J = 1.71, 7.58 Hz, 1H), 7.48-7.54 (m, 1H), 7.44 (d, J = 8.56 Hz, 2H), 7.19 (d, J = 8.19 Hz, 1H), 7.07 (s, 1H), 3.89 (s, 3H), 3.47-3.68 (m, 4H), 1.98- 2.10 (m, 4H).MF-PGDH-08866.1% / 98.39%342.11 for C19H19ClN 2O2 / 343.2 (M + 1)δ 10.67 (s, 1H), 7.77 (d, J = 8.56 Hz, 2H), 7.44-7.61 (m, 4H), 7.37 (d, J = 8.56 Hz, 2H), 3.36-3.68 (m, 4H), 1.57-1.66 (m, 2H), 1.42- 1.56 (m, 4H).MF-PGDH-0892.49% / 93.52%338.16 for C20H22N2 O3 / 339.2 (M + 1)δ 10.36 (s, 1H), 7.80-7.86 (m, 2H), 7.52-7.56 (m, 1H), 7.43-7.49 (m, 2H), 7.35-7.39 (m, 2H), 7.15- 7.19 (m, 1H), 3.84-3.85 (s, 3H), 3.34-3.64 (m, 4H), 1.46-1.65 (m, 6H).MF-PGDH-04390% / 94.19%338.16 for C20H22N2 O3 / 339.1 (M + 1)δ 9.53 (s, 1H), 7.98-8.01 (m, 2H), 7.71-7.76 (m, 1H), 7.48-7.51 (m, 2H), 7.19-7.21 (m, 1H), 7.09-7.12 (m, 1H), 6.92-7.01 (m, 1H), 3.82 (s, 3H), 3.60 (brs, 2H), 3.21 (brs, 2H), 1.41-1.72 (m, 6H).MF-PGDH-04423.69% / 99.96%352.18 for C21H24N2 O3 / 353.1 (M + 1)δ 7.08-7.31 (m, 6H), 6.93 (brd, J = 8.19 Hz, 1H), 6.84 (brt, J = 7.46 Hz, 1H), 3.68 (s, 3H), 3.50 (br s, 2H), 3.22 (s, 3H), 3.00-3.13 (m, 2H), 1.53-1.61 (m, 2H), 1.24- 1.52 (m, 4H).MF-PGDH-0042.7% / 99.50%338.12 for C20H19ClN 2O / 339.0 (M + 1)δ 7.79 (d, J = 3.4 Hz, 1H), 7.73- 7.68 (m, 2H), 7.64-7.58 (m, 3H), 7.50-7.47 (m, 1H), 7.26-7.22 (m, 1H), 6.79 (dd, J = 0.6, 3.3 Hz, 1H), 3.48 (br s, 4H), 1.62 (br d, J = 4.4 Hz, 2H), 1.52 (br s, 4H).MF-PGDH-0053.5% / 99.35%372.08 for C20H18C12 N2O / 372.9 317 (M + 1)δ 8.08 (s, 1H), 7.76-7.75 (m, 1H), 7.66-7.61 (m, 3H), 7.59 (d, J = 1.5 Hz, 1H), 7.50-7.53 (m, 1H), 7.31-7.35 (m, 1H), 3.34-3.65 (m, 4H), 1.62 (br d, J = 3.9 Hz, 2H), 1.44-1.58 (m, 4H).MF-PGDH-0532% / 98.66%338.12 for C20H19ClN 2O / 339.2 (M + 1)1H NMR (400 MHz, DMSO-d6): δ 11.65 (brs, 1H), 7.93-7.88 (m, 2H), 7.72-7.68 (m, 2H), 7.51-7.42 (m, 2H), 7.29-7.26 (m, 1H), 7.13- 7.09 (m, 1H), 3.62-3.40 (m, 4H), 1.68-1.43 (m, 6H).MF-PGDH-05481.4% / 99.81%352.13 for C21H21ClN 2O / 353.2 (M + 1)δ 7.93-7.88 (m, 2H), 7.70-7.65 (m, 2H), 7.57 (d, J = 0.7 Hz, 1H), 7.46 (t, J = 7.9 Hz, 1H), 7.29 (ddd, J = 0.9, 2.1, 8.0 Hz, 1H), 7.16 (dd, J = 1.3, 8.19 Hz, 1H), 3.87 (s, 3H), 3.66-3.40 (m, 4H), 1.67-1.48 (m, 6H).MF-PGDH-0577.0% / 95.07%354.15 for C21H23ClN 2O / 355.2 (M + 1)δ 7.42-7.37 (m, 1H), 7.30 (t, J = 2.0 Hz, 1H), 7.23 (ddd, J = 0.9, 2.1, 8.1 Hz, 1H), 7.17 (ddd, J = 0.9, 2.0, 8.1 Hz, 1H), 7.10 (d, J = 1.8 Hz, 1H), 6.97 (dd, J = 2.0, 8.4 Hz, 1H), 6.64 (d, J = 8.4 Hz, 1H), 3.63-3.58 (m, 2H), 3.44 (br s, 4H), 2.81-2.77 (m, 2H), 1.99- 1.92 (m, 2H), 1.64-1.56 (m, 2H), 1.48 (br d, J = 3.7 Hz, 4H).MF-PGDH-0588.2% / 98.34%368.13 for C21H21ClN 2O2 / 369.0 (M + 1)δ 7.60-7.52 (m, 2H), 7.46 (t, J = 1.7 Hz, 1H), 7.33-7.26 (m, 2H), 7.12-7.08 (m, 1H), 6.25 (d, J = 8.3 Hz, 1H), 3.69-3.35 (m, 4H), 3.07 (br t, J = 7.3 Hz, 2H), 2.76-2.71 (m, 2H), 1.64- 1.56 (m, 2H), 1.55-1.42 (m, 4H).MF-PGDH-0064.41% / 99.75%339.11 for C19H18ClN 3O / 340.0 (M + 1)δ 8.49 (s, 1H), 7.96-7.89 (m, 2H), 7.94-7.88 (m, 1H), 7.85-7.81 (m, 1H), 7.64-7.61 (m, 1H), 7.55-7.51 (m, 2H), 3.69-3.31 (m, 4H), 1.71- 1.42 (m, 6H).MF-PGDH-00715.7% / 98.0%339.11for C19H18ClN 3O / 340.0 (M + 1)δ 8.64-8.61 (m, 1H), 7.92 (s, 1H), 7.79 (s, 1H), 7.68-7.62 (m, 2H), 7.59-7.54 (m, 1H), 7.52-7.49 (m, 1H), 6.99-6.95 (m, 1H), 3.69-3.35 (m, 4H), 1.69-1.45 (m, 6H).MF-PGDH-01145.29% / 97.16%340.11for C18H17ClN 4O / 341.0 (M + 1)δ 8.21 (s, 1H), 8.03-8.00 (m, 2H), 7.92-7.89 (m, 1H), 7.76-7.65 (m, 3H), 3.73-3.52 (m, 2H), 1.70-1.21 (m, 8H).MF-PGDH-0129.9% / 98.76%340.11for C18H17ClN 4O / 341.0 (M + 1)δ 9.33 (d, J = 2.1 Hz, 1H), 8.94 (s, 1H), 8.73 (d, J = 2.1 Hz, 1H), 8.28 (t, J = 1.8 Hz, 1H), 8.14-8.10 (m, 1H), 7.49 (t, J = 7.9 Hz, 1H), 7.34- 7.30 (m, 1H), 3.66-3.43 (m, 4H), 1.67-1.54 (m, 6H).MF-DH-15035.7% / 99.98%339.15 for C18H18FN5 O / 340.1 (M + 1)δ 10.10 (d, J = 1.2 Hz, 1H), 8.58- 8.64 (m, 2H), 8.36 (d, J = 3.9 Hz, 1H), 8.30 (s, 1H), 7.02 (d, J = 3.9 Hz, 1H), 4.82-5.02 (m, 1H), 3.64-3.90 (m, 2H), 3.34-3.41 (m, 1H), 3.11-3.26 (m, 1H), 2.50 (s, 3H), 1.60-2.08 (m, 4H).MF-DH-1516.1% / 99.45%373.11 for C18H17ClF N5O / 374.0 (M + 1)δ 9.98 (s, 1H), 8.63 (s, 2H), 8.46 (s, 1H), 8.36 (s, 1H), 4.82-5.04 (m, 1H), 3.84 (br s, 1H), 3.65- 3.76 (m, 1H), 3.14-3.23 (m, 1H), 2.70 (s, 3H), 1.70-2.03 (m, 4H).MF-DH-16117.0% / 99.13%408.16 for C20H20F4N 4O / 409.1 (M + 1)δ 8.39-8.43 (m, 1H), 8.30-8.33 (m, 1H), 8.16 (d, J = 2.45 Hz, 1H), 7.35-7.41 (m, 2H), 7.29 (s, 1H), 5.52-5.60 (m, 1H), 4.82-5.01 (m, 1H), 3.36-3.71 (m, 4H), 2.74-2.83 (m, 1H), 2.61-2.69 (m, 1H), 1.67- 2.04 (m, 6H).MF-DH-16418.6% / 92.70%340.17 for C19H21FN4 O / 341.1 (M + 1)δ 8.89 (s, 1H), 8.77 (s, 2H), 7.17 (s, 1H), 7.03 (brd, J = 8.3 Hz, 1H), 6.72-6.75 (m, 1H), 4.80-4.96 (m, 1H), 3.66 (t, J = 5.8 Hz, 2H), 3.45- 3.60 (m, 4H), 2.81 (t, J = 6.4 Hz, 2H), 1.86-2.00 (m, 4H), 1.65-1.72 (m, 2H).MF-DH-1627.5% / 99.77%354.19 for C20H23FN4 O / 355.1 (M + 1)δ 8.55 (s, 1H), 8.24-8.32 (m, 1H), 8.08 (d, J = 2.6 Hz, 1H), 7.37 (d, J = 8.3 Hz, 1H), 7.28-7.35 (m, 1H), 7.17 (dd, J = 1.7, 8.3 Hz, 1H), 4.82-5.01 (m, 1H), 3.83 (t, J = 6.2 Hz, 2H), 3.38-3.67 (m, 4H), 2.86-2.97 (m, 1H), 2.04-2.13 (m, 1H), 1.81-2.01 (m, 2H), 1.58-1.79 (m, 3H), 1.29 (d, J = 7.0 Hz, 3H).MF-DH-16016.7% / 98.63%368.20 for C21H25FN4 O / 369.1 (M + 1)δ 8.53-8.58 (s, 1H), 8.27-8.30 (s, 1H), 8.08-8.1.1 (m, 1H), 7.42 (s, 1H), 7.32-7.39 (m, 1H), 7.11-7.17 (m, 1H), 4.82-5.00 (m, 1H), 3.82- 3.91 (m, 2H), 3.41-3.71 (m, 4H), 1.81-1.98 (m, 2H), 1.68-1.81 (m, 4H), 1.29 (s, 6H)MF-DH-16716.5% / 99.68%373.11 for C18H17ClF N5O / 374.0 (M + 1)δ 9.82 (s, 1H), 8.56-8.63 (m, 1H), 8.50-8.56 (m, 2H), 8.18 (d, J = 1.83 Hz, 1H), 4.85-5.04 (m, 1H), 3.40-3.88 (m, 4H), 2.58 (s, 3H), 1.69-2.05 (m, 4H).MF-DH-1689.5% / 98.46%373.11 for C18H17ClF N5O / 374.0 (M + 1)δ 8.76 (d, J = 2.4 Hz, 1H), 8.59 (d, J = 2.1 Hz, 1H), 8.42 (d, J = 1.6 Hz, 1H), 8.15-8.23 (m, 2H), 4.83-5.02 (m, 1H), 3.38-3.79 (m, 4H), 2.43 (s, 3H), 1.85-2.02 (m, 2H), 1.69- 1.83 (m, 2H).MF-DH-1595.48% / 99.36%342.15 for C18H19FN4 O2 / 343.1 (M + 1)1H NMR (400 MHz, DMSO-d6): δ 8.64 (s, 1H), 8.31 (br s, 1H), 8.14 (d, J = 2.4 Hz, 1H), 7.55 (d, J = 8.3 Hz, 1H), 6.86-7.00 (m, 2H), 4.81-5.01 (m, 1H), 4.23-4.38 (m, 2H), 4.02 (br d, J = 4.2 Hz, 2H), 3.39-3.67 (m, 4H), 1.82-1.99 (m, 2H), 1.65-1.79 (m, 2H).MF-DH-20730.3% / 99.84%366.16 for C21H22N2 O4 / 367.2 (M + 1)1H NMR (400 MHz, DMSO-d6): δ 6.89-7.00 (m, 2H), 6.69-6.82 (m, 3H), 6.53 (d, J = 8.2 Hz, 1H), 6.05 (s, 2H), 4.24-4.33 (m, 2H), 3.57-3.69 (m, 2H), 3.42 (br s, 4H), 1.59 (br d, J = 4.4 Hz, 2H), 1.40-1.53 (m, 4H).MF-DH-2092.2% / 93.69%352.18 for C21H24N2 O3 / 353.2 (M + 1)1H NMR (400 MHz, DMSO-d6): δ 7.24 (brd, J = 8.8 Hz, 2H), 7.00 (br d, J = 8.8 Hz, 2H), 6.78 (d, J = 1.5 Hz, 1H), 6.71 (br d, J = 8.4 Hz, 1H), 6.49 (s, 1H), 4.30 (br s, 2H), 3.77 (s, 3H), 3.60- 3.72 (m, 2H), 3.43 (br s, 4H), 1.59 (br d, J = 3.7 Hz, 2H), 1.47 (br s, 4H).MF-DH-20320.36% / 99.43%303.17 for C17H22FN3 O / 304.1 (M + 1)δ 8.33 (s, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.69 (s, 1H), 7.28 (brd, J = 8.4 Hz, 1H), 4.82-5.01 (m, 1H), 3.37-3.68 (m, 4H), 1.82-1.99 (m, 2H), 1.67-1.77 (m, 11H).MF-DH-1657.2% / 97.23%326.15 for C18H19FN4 O / 327.1 (M + 1)δ 8.26-8.37 (m, 3H), 8.11 (d, J = 2.6 Hz, 1H), 7.31 (s, 1H), 7.23- 7.30 (m, 1H), 4.82-5.00 (m, 1H), 4.18 (t, J = 8.7 Hz, 2H), 3.41-3.66 (m, 4H), 3.22-3.28 (m, 2H), 1.81- 1.99 (m, 2H), 1.64-1.78 (m, 2H).MF-DH-31161.3% / 99.78%307.10 for C14H17N3 O3S / 308.1 (M + 1)δ 8.49-8.42 (m, 1H), 8.17 (d, J = 1.7 Hz, 1H), 7.81 (d, J = 3.9 Hz, 1H), 6.84 (d, J = 3.9 Hz, 1H), 3.74 (s, 3H), 3.69-3.47 (m, 2H), 1.67-1.45 (m, 6H).MF-DH-31246.4% / 99.99%383.13 for C20H21N3 O3S / 384.1 (M + 1)δ 8.39-8.35 (m, 1H), 8.08 (d, J = 1.8 Hz, 1H), 8.04-7.95 (m, 3H), 7.43 (brd, J = 8.1 Hz, 2H), 6.86 (d, J = 4.0 Hz, 1H), 3.69-3.49 (m, 2H), 3.44-3.32 (m, 2H), 2.34 (s, 3H), 1.65-1.42 (m, 6H).MF-DH-31834.1% / 97.63%345.16 for C20H19N5 O / 346.2 (M + 1)δ 9.19 (s, 1H), 8.36 (d, J = 1.9 Hz, 1H), 8.15 (d, J = 1.9 Hz, 1H), 8.09 (s, 1H), 8.06-7.98 (m, 1H), 7.77-7.66 (m, 3H), 6.85-6.82 (m, 1H), 3.78-3.36 (m, 4H), 1.69-1.48 (m, 6H).MF-DH-3203.5% / 99.12%320.16 for C19H20N4 O / 321.2 (M + 1)δ 8.95 (s, 1H), 8.44-8.35 (m, 2H), 8.21-8.08 (m, 3H), 6.84 (d, J = 3.7 Hz, 1H), 3.64-3.37 (m, 4H), 2.42 (s, 3H), 1.68-1.50 (m, 6H).MF-DH-34243.6% / 99.48%348.14 for C20H17FN4 O / 349.0 (M + 1)δ 8.43 (d, J = 2.0 Hz, 1H), 8.34- 8.25 (m, 2H), 8.23-8.18 (m, 2H), 8.08-8.02 (m, 2H), 6.89 (d, J = 3.8 Hz, 1H), 5.02-4.84 (m, 1H), 3.84-3.39 (m, 4H), 2.05-1.69 (m, 4H).MF-DH-34439.6% / 99.64%348.14 for C20H17FN4 O / 349.2 (M + 1)δ 8.50-8.47 (m, 1H), 8.44-8.42 (m, 1H), 8.39-8.35 (m, 1H), 8.22- 8.16 (m, 2H), 7.85-7.76 (m, 2H), 6.86 (d, J = 3.8 Hz, 1H), 5.03-4.84 (m, 1H), 3.77-3.36 (m, 4H), 2.02-1.70 (m, 4H).MF-DH-36663.9% / 99.68%349.19 for C20H23N5 O / 350.2 (M + 1)δ 8.43 (d, J = 2.4 Hz, 1H), 8.29 (d, J = 2.0 Hz, 1H), 8.10 (d, J = 2.0 Hz, 1H), 7.92-7.86 (m, 2H), 6.82-6.73 (m, 2H), 3.69-3.34 (m, 4H), 3.09 (s, 6H), 1.67-1.49 (m, 6H).MF-DH-38951.0% / 99.81%331.14 for C19H17N5 O / 332.2 (M + 1)δ 9.44-9.36 (m, 1H), 8.70 (dd, J = 8.5, 2.1 Hz, 1H), 8.32 (s, 1H), 8.24-8.12 (m, 2H), 8.12-8.04 (m, 1H), 6.84 (d, J = 3.7 Hz, 1H), 3.59-3.25 (m, 4H), 1.58-1.38 (m, 6H).MF-DH-39754.6% / 99.77%332.14 for C18H16N6 O / 333.2 (M + 1)δ 9.82 (s, 2H), 8.45 (d, J = 1.9 Hz, 1H), 8.36 (d, J = 3.9 Hz, 1H), 8.21 (d, J = 1.9 Hz, 1H), 7.00 (d, J = 3.9 Hz, 1H), 3.74-3.33 (m, 4H), 1.68-1.46 (m, 6H).MF-DH-31930.5% / 99.93%345.16 for C20H19N5 O / 346.1 (M + 1)δ 13.25 (br s, 1H), 8.35 (s, 1H), 8.23-8.01 (m, 3H), 7.99-7.97 (m, 1H), 7.82-7.69 (m, 2H), 6.81 (s, 1H), 3.72-3.42 (m, 4H), 1.71-1.42 (m, 6H).MF-DH-33733.3% / 98.99%465.22 for C28H27N5 O2 / 466.1 (M + 1)δ 8.31 (d, J = 1.9 Hz, 1H), 8.21- 8.19 (m, 1H), 8.19-8.09 (m, 2H), 8.00 (d, J = 3.5 Hz, 1H), 7.87 (d, J = 9.0 Hz, 1H), 7.83-7.74 (m, 1H), 7.27-7.22 (m, 2H), 6.91- 6.86 (m, 2H), 6.80-6.77 (m, 1H), 5.65 (s, 2H), 3.70 (s, 3H), 3.64- 3.34 (m, 4H), 1.68-1.45 (m, 6H).MF-DH-34034.1% / 99.35%465.22 for C28H27N5 O2 / 466.2 (M + 1)δ 8.55 (s, 1H), 8.32 (s, 1H), 8.10 (br d, J = 14.5 Hz, 2H), 8.06- 7.93 (m, 1H), 7.76 (br d, J = 9.2 Hz, 1H), 7.72-7.63 (m, 1H), 7.33 (br d, J = 8.4 Hz, 2H), 6.93 (br d, J = 8.4 Hz, 2H), 6.88-6.73 (m, 1H), 5.61 (s, 2H), 3.73 (s, 3H), 3.66-3.37 (m, 4H), 1.69- 1.47 (m, 6H).MF-DH-34327.5% / 98.89%366.15 for C20H19FN4 O2 / 367.1 (M + 1)δ 8.42 (d, J = 2.0 Hz, 1H), 8.22- 8.11 (m, 2H), 8.06 (s, 5H), 7.43- 7.40 (m, 1H), 6.86-6.83 (m, 1H), 5.03-4.84 (m, 1H), 3.75-3.36 (m, 4H), 2.03-1.85 (m, 2H), 1.84-1.69 (m, 2H).MF-DH-34521.4% / 99.38%366.15 for C20H19FN4 O2 / 367.1 (M + 1)δ 8.40 (d, J = 2.0 Hz, 1H), 8.31 (t, J = 1.8 Hz, 1H), 8.19 (d, J = 2.0 Hz, 1H), 8.16-8.03 (m, 3H), 7.86 (s, 1H), 7.69-7.61 (m, 1H), 7.53-7.48 (m, 1H), 6.84 (d, J = 3.6 Hz, 1H), 5.03-4.84 (m, 1H), 3.77-3.37 (m, 4H), 2.03-1.87 (m, 2H), 1.84-1.69 (m, 2H).MF-DH-36520.5% / 96.50%349.15 for C19H19N5 O2 / 350.2 (M + 1)δ 9.27 (brs, 1H), 8.62 (brd, J = 7.1 Hz, 1H), 8.40 (br s, 1H), 8.29-8.10 (m, 4H), 7.69 (br s, 1H), 6.90 (brd, J = 3.1 Hz, 1H), 3.73-3.40 (m, 4H), 1.68-1.50 (m, 6H).MF-DH-38443.6% / 99.72%350.15 for C18H18N6 O2 / 351.2 (M + 1)δ 9.63 (s, 2H), 8.43 (d, J = 1.7 Hz, 1H), 8.31 (d, J = 3.8 Hz, 1H), 8.28-8.23 (m, 1H), 8.23-8.17 (m, 1H), 7.84 (brs, 1H), 6.95 (d, J = 3.8 Hz, 1H), 3.70-3.35 (m, 4H), 1.70-1.49 (m, 6H).MF-DH-39440.3% / 96.60%384.14 for C20H18F2N 4O2 / 385.2 (M + 1)δ 8.45 (d, J = 2.0 Hz, 1H), 8.23 (d, J = 1.8 Hz, 1H), 8.15 (d, J = 3.8 Hz, 1H), 8.06 (s, 5H), 7.43 (br s, 1H), 6.85 (d, J = 3.8 Hz, 1H), 3.78-3.52 (m, 4H), 2.08 (br s, 4H).MF-DH-34714.2% / 99.30%353.15 for C20H20FN3 O2 / 354.2 (M + 1)δ 8.37 (d, J = 2.0 Hz, 1H), 8.16 (d, J = 2.0 Hz, 1H), 8.01 (d, J = 3.6 Hz, 1H), 7.86-7.80 (m, 2H), 7.49 (d, J = 8.6 Hz, 2H), 6.79 (d, J = 3.6 Hz, 1H), 5.27 (t, J = 5.8 Hz, 1H), 5.02-4.83 (m, 1H), 4.57 (d, J = 5.8 Hz, 2H), 3.78-3.43 (m, 4H), 2.03-1.70 (m, 4H).MF-DH-34828.0% / 97.73%353.15 for C20H20FN3 O2 / 354.2 (M + 1)δ 8.38 (d, J = 2.0 Hz, 1H), 8.17 (d, J = 2.0 Hz, 1H), 8.00 (d, J = 3.6 Hz, 1H), 7.81 (s, 1H), 7.78- 7.68 (m, 1H), 7.51 (t, J = 7.8 Hz, 1H), 7.33 (d, J = 7.8 Hz, 1H), 6.80 (d, J = 3.8 Hz, 1H), 5.43- 5.13 (m, 1H), 5.03-4.85 (m, 1H), 4.61 (s, 2H), 3.71-3.38 (m, 4H), 2.04-1.85 (m, 2H), 1.84-1.67 (m, 2H).MF-DH-37063.0% / 99.30%353.15 for C20H20FN3 O2 / 354.2 (M + 1)δ 8.37 (d, J = 2.0 Hz, 1H), 8.16 (d, J = 2.0 Hz, 1H), 8.01 (d, J = 3.6 Hz, 1H), 7.86-7.80 (m, 2H), 7.49 (d, J = 8.6 Hz, 2H), 6.79 (d, J = 3.6 Hz, 1H), 5.27 (t, J = 5.8 Hz, 1H), 5.02-4.83 (m, 1H), 4.57 (d, J = 5.8 Hz, 2H), 3.78-3.43 (m, 4H), 2.03-1.70 (m, 4H).MF-DH-37134.6% / 95.05%363.19 for C22H25N3 O2 / 364.2 (M + 1)δ 8.32 (d, J = 2.0 Hz, 1H), 8.11 (d, J = 2.0 Hz, 1H), 7.99 (d, J = 3.6 Hz, 1H), 7.81-7.72 (m, 2H), 7.68-7.58 (m, 2H), 6.78 (d, J = 3.6 Hz, 1H), 5.10 (s, 1H), 3.64- 3.33 (m, 4H), 1.68-1.51 (m, 6H), 1.49 (s, 6H).MF-DH-37456.3% / 97.83%353.15 for C20H20FN3 O2 / 354.2 (M + 1)δ 8.38 (d, J = 2.0 Hz, 1H), 8.17 (d, J = 2.0 Hz, 1H), 8.00 (d, J = 3.6 Hz, 1H), 7.81 (s, 1H), 7.78- 7.68 (m, 1H), 7.51 (t, J = 7.8 Hz, 1H), 7.33 (d, J = 7.8 Hz, 1H), 6.80 (d, J = 3.8 Hz, 1H), 5.43- 5.13 (m, 1H), 5.03-4.85 (m, 1H), 4.61 (s, 2H), 3.71-3.38 (m, 4H), 2.04-1.85 (m, 2H), 1.84-1.67 (m, 2H).MF-DH-37538.65% / 96.62%363.19 for C22H25N3 O2 / 364.1 (M + 1)δ 8.32 (d, J = 2.0 Hz, 1H), 8.12 (d, J = 2.0 Hz, 1H), 7.98 (d, J = 3.8 Hz, 1H), 7.90-7.84 (m, 1H), 7.76-7.65 (m, 1H), 7.52-7.43 (m, 2H), 6.79 (d, J = 3.6 Hz, 1H), 5.13 (s, 1H), 3.66-3.35 (m, 4H), 1.67-1.51 (m, 6H), 1.49 (s, 6H).MF-DH-32414.6% / 99.78%403.15 for C21H20F3N 3O2 / 404.1 (M + 1)δ 8.34 (d, J = 2.0 Hz, 1H), 8.16 (d, J = 2.1 Hz, 1H), 7.93 (d, J = 3.6 Hz, 1H), 7.76-7.71 (m, 2H), 7.14-7.09 (m, 2H), 6.76 (d, J = 3.6 Hz, 1H), 4.65-4.27 (m, 1H), 3.83 (s, 3H), 3.14-2.78 (m, 2H), 2.71-2.55 (m, 2H), 1.93-1.77 (m, 2H), 1.53-1.41 (m, 2H).MF-DH-32532.0% / 99.14%411.19 for C26H25N3 O2 / 412.1 (M + 1)δ 8.38 (d, J = 2.0 Hz, 1H), 8.18 (d, J = 2.0 Hz, 1H), 7.93 (d, J = 3.6 Hz, 1H), 7.78-7.71 (m, 2H), 7.34-7.27 (m, 4H), 7.27-7.17 (m, 1H), 7.16-7.08 (m, 2H), 6.77-6.76 (m, 1H), 4.82-4.38 (m, 1H), 3.83 (s, 3H), 3.20-2.89 (m, 2H), 2.88-2.58 (m, 2H), 1.92- 1.62 (m, 4H).MF-DH-32624.5% / 98.96%383.16 for C24H21N3 O2 / 384.1 (M + 1)δ 8.62 (d, J = 2.0 Hz, 1H), 8.41 (d, J = 2.0 Hz, 1H), 7.94 (d, J = 3.6 Hz, 1H), 7.77-7.70 (m, 2H), 7.45-7.35 (m, 4H), 7.35-7.23 (m, 1H), 7.16-7.08 (m, 2H), 6.79 (d, J = 3.8 Hz, 1H), 4.82-4.39 (m, 3H), 4.13-3.91 (m, 2H), 3.83 (s, 3H).MF-DH-32721.2% / 99.33%418.16 for C21H21F3N 4O2 / 419.2 (M + 1)δ 8.33 (d, J = 2.0 Hz, 1H), 8.13 (d, J = 2.0 Hz, 1H), 7.94 (d, J = 3.6 Hz, 1H), 7.78-7.69 (m, 2H), 7.16-7.08 (m, 2H), 6.76 (d, J = 3.6 Hz, 1H), 3.83 (s, 3H), 3.66- 3.39 (m, 4H), 3.26-3.22 (m, 2H), 2.71-2.62 (m, 4H).MF-DH-32811.2% / 91.01%363.19 for C22H25N3 O2 / 364.1 (M + 1)δ 8.26 (d, J = 2.0 Hz, 1H), 8.07 (d, J = 2.0 Hz, 1H), 7.92 (d, J = 3.6 Hz, 1H), 7.79-7.68 (m, 2H), 7.17-7.06 (m, 2H), 6.74 (d, J = 3.6 Hz, 1H), 4.66-4.17 (m, 2H), 3.83 (s, 3H), 1.91-1.77 (m, 1H), 1.71-1.61 (m, 2H), 1.58-1.32 (m, 3H), 1.27-1.09 (m, 7H).MF-DH-329 (Cis)54.6% / 98.52%363.19 for C22H25N3 O2 / 364.1 (M + 1)δ 8.31 (d, J = 2.0 Hz, 1H), 8.10 (d, J = 2.0 Hz, 1H), 7.93 (d, J = 3.6 Hz, 1H), 7.78-7.70 (m, 2H), 7.16-7.07 (m, 2H), 6.76 (d, J = 3.6 Hz, 1H), 4.56-4.34 (m, 1H), 3.83 (s, 3H), 3.73-3.51 (m, 1H), 2.77-2.57 (m, 1H), 2.38-2.16 (m, 1H), 1.80 (br d, J = 12.8 Hz, 1H), 1.68-1.56 (m, 2H), 0.95- 0.66 (m, 7H).MF-DH-3677.34% / 98.31%406.20 for C23H26N4 O3 / 407.3 (M + 1)δ 8.58 (br s, 1H), 8.35 (d, J = 1.7 Hz, 1H), 8.15-7.99 (m, 6H), 6.82 (d, J = 3.7 Hz, 1H), 3.61-3.38 (m, 8H), 3.27 (s, 3H), 1.66-1.46 (m, 6H).MF-DH-36824.2% / 99.85%362.17 for C21H22N4 O2 / 363.2 (M + 1)δ 8.51 (brd, J = 4.5 Hz, 1H), 8.37 (d, J = 2.0 Hz, 1H), 8.15-7.99 (m, 6H), 6.84 (d, J = 3.7 Hz, 1H), 3.71-3.35 (m, 4H), 2.82 (d, J = 4.4 Hz, 3H), 1.66-1.54 (m, 4H).MF-DH-36918.5% / 98.31%376.19 for C22H24N4 O2 / 377.2 (M + 1)δ 8.36 (d, J = 2.0 Hz, 1H), 8.18- 8.06 (m, 2H), 8.06-7.97 (m, 2H), 7.60 (d, J = 8.6 Hz, 2H), 6.83 (d, J = 3.8 Hz, 1H), 3.68-3.35 (m, 4H), 3.04-2.96 (m, 6H), 1.67- 1.49 (m, 6H).MF-DH-28543.4% / 99.84%353.15 for C20H20FN3 O2 / 354.2 (M + 1)δ 8.36-8.34 (m, 1H), 8.16-8.14 (m, 1H), 7.95-7.92 (m, 1H), 7.76-7.72 (m, 2H), 7.13-7.10 (m, 2H), 6.77-6.75 (m, 1H), 5.01- 4.86 (m, 1H), 3.83 (s, 3H), 3.73- 3.52 (m, 3H), 3.38-3.33 (m, 1H), 2.01-1.73 (m, 4H).MF-DH-29434.13% / 98.52%335.16 for C20H21N3 O2 / 336.2 (M + 1)δ 8.34 (d, J = 1.7 Hz, 1H), 8.12 (d, J = 1.7 Hz, 1H), 8.05 (d, J = 3.7 Hz, 1H), 7.52-7.44 (m, 3H), 6.98-6.94 (m, 1H), 6.80-6.78 (m, 1H), 3.84 (s, 3H), 3.66-3.37 (m, 4H), 1.66-1.51 (m, 6H).MF-DH-29540.2% / 99.52%340.11 for C18H17ClN 4O / 341.1 (M + 1)δ 9.23-9.21 (m, 1H), 8.68-8.62 (m, 2H), 8.41-8.39 (m, 1H), 8.23-8.15 (m, 2H), 6.90-6.87 (m, 1H), 3.68-3.40 (m, 4H), 1.65-1.52 (m, 6H).MF-DH-29652.7% / 97.61%336.16 for C19H20N4 O2 / 337.2 (M + 1)δ 8.81 (s, 1H), 8.39-8.30 (m, 2H), 8.19-8.12 (m, 2H), 7.99 (br s, 1H), 6.85 (d, J = 3.7 Hz, 1H), 3.93 (s, 3H), 3.68-3.35 (m, 4H), 1.68-1.47 (m, 6H).MF-DH-29745.8% / 99.26%335.16 for C20H21N3 O2 / 336.1 (M + 1)δ 8.31 (d, J = 1.6 Hz, 1H), 8.10 (d, J = 1.7 Hz, 1H), 7.93 (d, J = 3.5 Hz, 1H), 7.74 (br d, J = 8.8 Hz, 2H), 7.11 (br d, J = 8.9 Hz, 2H), 6.75 (d, J = 3.5 Hz, 1H), 3.83 (s, 3H), 3.65-3.35 (m, 4H), 1.68- 1.48 (m, 6H).MF-DH-29831.4% / 99.99%330.15 for C20H18N4 O / 331.1 (M + 1)δ 8.42-8.36 (m, 1H), 8.33-8.25 (m, J = 8.7 Hz, 2H), 8.23-8.13 (m, 2H), 8.04 (br d, J = 8.6 Hz, 2H), 6.88 (d, J = 3.7 Hz, 1H), 3.70-3.34 (m, 4H), 1.67-1.47 (m, 6H).MF-DH-30061.4% / 99.46%330.15 for C20H18N4 O / 331.1 (M + 1)δ 8.48 (s, 1H), 8.42-8.33 (m, 2H), 8.19-8.12 (m, 2H), 7.86- 7.74 (m, 2H), 6.85 (d, J = 3.8 Hz, 1H), 3.67-3.35 (m, 4H), 1.68- 1.48 (m, 6H).MF-DH-30257.5% / 99.57%348.45 for C21H24N4 O / 349.2 (M + 1)δ 8.32 (d, J = 2.0 Hz, 1H), 8.10 (d, J = 2.0 Hz, 1H), 7.98 (d, J = 3.6 Hz, 1H), 7.36-7.29 (m, 1H), 7.16-7.08 (m, 2H), 6.78-6.71 (m, 2H), 3.66-3.34 (m, 4H), 2.97 (s, 6H), 1.67-1.49 (m, 6H).MF-DH-30518.4% / 99.14%348.20 for C21H24N4 O / 349.2 (M + 1)δ 8.33-8.24 (m, 1H), 8.13-8.03 (m, 1H), 7.85 (d, J = 3.4 Hz, 1H), 7.58 (br d, J = 8.9 Hz, 2H), 6.87 (br d, J = 8.8 Hz, 2H), 6.72 (d, J = 3.5 Hz, 1H), 3.65-3.37 (m, 4H), 2.96 (s, 6H), 1.67-1.47 (m, 6H).MF-DH-30614.2% / 99.73%349.18 for C21H23N3 O2 / 350.2 (M + 1)δ 8.31 (d, J = 2.0 Hz, 1H), 8.10 (d, J = 2.0 Hz, 1H), 7.93 (d, J = 3.6 Hz, 1H), 7.72 (d, J = 9.0 Hz, 2H), 7.10 (d, J = 9.0 Hz, 2H), 6.75 (d, J = 3.6 Hz, 1H), 4.10 (d, J = 7.0 Hz, 2H), 3.63-3.36 (m, 4H), 1.68-1.48 (m, 6H), 1.39-1.34 (m, 3H).MF-DH-30968.3% / 99.16%383.13 for C20H21N3 O3S / 384.2 (M + 1)δ 8.50 (t, J = 1.8 Hz, 1H), 8.40- 8.30 (m, 2H), 8.21-8.14 (m, 2H), 7.94-7.83 (m, 2H), 6.87 (d, J = 3.8 Hz, 2H), 3.70-3.34 (m, 4H), 3.32 (s, 3H), 1.67-1.46 (m, 6H).MF-DH-31057.3% / 99.25%383.13 for C20H21N3 O3S / 384.1 (M + 1)δ 8.39 (d, J = 2.0 Hz, 1H), 8.33- 8.27 (m, 2H), 8.21-8.08 (m, 4H), 6.88 (d, J = 3.9 Hz, 1H), 3.71- 3.34 (m, 4H), 3.28 (s, 3H), 1.68- 1.49 (m, 6H).MF-DH-31717.5% / 96.14%321.16 for C18H19N5 O / 322.2 (M + 1)δ 8.37 (d, J = 2.0 Hz, 1H), 8.12 (d, J = 2.0 Hz, 1H), 8.09-7.98 (m, 2H), 7.27 (d, J = 1.8 Hz, 1H), 7.10 (dd, J = 5.8, 2.0 Hz, 1H), 6.82 (d, J = 3.9 Hz, 1H), 6.15 (s, 2H), 3.67-3.34 (m, 4H), 1.68- 1.50 (m, 6H).MF-DH-32111.5% / 93.50%322.14 for C18H18N4 O2 / 323.1 (M + 1)δ 11.97-11.85 (m, 1H), 8.30 (d, J = 1.9 Hz, 1H), 8.09 (d, J = 1.9 Hz, 1H), 7.85 (br d, J = 3.6 Hz, 3H), 6.73 (d, J = 3.5 Hz, 1H), 6.53-6.49 (m, 1H), 3.71-3.36 (m, 4H), 1.67-1.44 (m, 6H).MF-DH-32221.4% / 99.58%321.16 for C18H19N5 O / 322.2 (M + 1)δ 8.33 (d, J = 2.0 Hz, 1H), 8.21- 8.07 (m, 2H), 8.01-7.90 (m, 2H), 7.50 (t, J = 2.3 Hz, 1H), 6.79 (d, J = 3.6 Hz, 2H), 5.63 (s, 2H), 3.66-3.34 (m, 4H), 1.68-1.47 (m, 6H).MF-DH-32369.0% / 99.53%336.16 for C19H20N4 O2 / 337.2 (M + 1)δ 8.60 (d, J = 2.4 Hz, 1H), 8.32 (d, J = 2.0 Hz, 1H), 8.20 (dd, J = 8.9, 2.8 Hz, 1H), 8.13 (d, J = 2.0 Hz, 1H), 7.99 (d, J = 3.6 Hz, 1H), 7.03 (d, J = 8.9 Hz, 1H), 6.80 (d, J = 3.6 Hz, 1H), 3.93 (s, 3H), 3.71-3.35 (m, 4H), 1.67-1.49 (m, 6H).MF-DH-33635.5% / 98.03%321.16 for C18H19N5 O / 322.2 (M + 1)δ 8.36-8.17 (m, 2H), 8.08 (br s, 1H), 7.87-7.79 (m, 1H), 7.79- 7.69 (m, 1H), 6.78-6.67 (m, 1H), 6.59 (brd, J = 8.7 Hz, 1H), 6.15 (br s, 2H), 3.75-3.35 (m, 4H), 1.71-1.40 (m, 6H).MF-DH-29942.2% / 99.76%348.16 for C20H20N4 O2 / 349.2 (M + 1)δ 8.37 (d, J = 2.0 Hz, 1H), 8.18- 8.10 (m, 2H), 8.06 (s, 5H), 7.42 (br s, 1H), 6.84 (d, J = 3.8 Hz, 1H), 3.70-3.33 (m, 4H), 1.68- 1.47 (m, 6H).MF-DH-30147.4% / 99.94%348.16 for C20H20N4 O2 / 349.1 (M + 1)δ 8.39-8.28 (m, 2H), 8.18-8.03 (m, 4H), 7.87 (d, J = 7.8 Hz, 1H), 7.65 (t, J = 7.9 Hz, 1H), 7.50 (br s, 1H), 6.83 (d, J = 3.8 Hz, 1H), 3.68-3.34 (m, 4H), 1.67-1.48 (m, 6H).MF-DH-3038.4% / 98.61%334.18 for C20H22N4 O / 335.2 (M + 1)δ 8.33 (s, 1H), 8.13-8.11 (m, 1H), 8.00-7.98 (m, 1H), 7.79 (s, 1H), 7.73 (br d, J = 7.5 Hz, 1H), 7.50-7.46 (m, 1H), 7.36-7.32 (m, 1H), 6.80-6.78 (m, 1H), 3.81 (s, 2H), 3.66-3.38 (m, 4H), 1.66-1.52 (m, 6H).MF-DH-3049.6% / 95.06%334.18 for C20H22N4 O / 335.1 (M + 1)δ 8.33-8.32 (m, 1H), 8.12-8.11 (m, 1H), 8.01-7.99 (m, 1H), 7.82 (br d, J = 8.7 Hz, 2H), 7.54-7.50 (m, 2H), 6.79-6.77 (m, 1H), 3.83- 3.82 (m, 2H), 3.61-3.42 (m, 4H), 1.65-1.53 (m, 6H).MF-DH-30736.6% / 99.38%335.16 for C20H21N3 O2 / 336.2 (M + 1)δ 8.33 (d, J = 2.0 Hz, 1H), 8.12 (d, J = 2.0 Hz, 1H), 8.01 (d, J = 3.8 Hz, 1H), 7.83 (d, J = 8.5 Hz, 2H), 7.49 (d, J = 8.5 Hz, 2H), 6.78 (d, J = 3.6 Hz, 1H), 5.27 (t, J = 5.7 Hz, 1H), 4.57 (d, J = 5.8 Hz, 2H), 3.68-3.33 (m, 4H), 1.67-1.48 (m, 6H).MF-DH-30870.4% / 97.68%335.16 for C20H21N3 O2 / 336.2 (M + 1)δ 8.34 (d, J = 1.8 Hz, 1H), 8.12 (d, J = 1.8 Hz, 1H), 7.99 (d, J = 3.6 Hz, 1H), 7.81 (s, 1H), 7.78- 7.68 (m, 1H), 7.51 (t, J = 7.8 Hz, 1H), 7.43-7.22 (m, 1H), 6.79 (d, J = 3.5 Hz, 1H), 5.32 (t, J = 5.8 Hz, 1H), 4.61 (d, J = 5.8 Hz, 2H), 3.75-3.35 (m, 4H), 1.75- 1.35 (m, 6H).MF-DH-19167.5% / 95.24%387.11 for C20H19ClF N3O2 / 388.0 (M + 1)δ 8.43 (d, J = 1.71 Hz, 1H), 8.22 (s, 1H), 8.10 (d, J = 1.83 Hz, 1H), 7.72 (br d, J = 8.93 Hz, 2H), 7.12 (br d, J = 8.93 Hz, 2H), 5.03-4.83 (m, 1H), 3.83 (s, 3H), 3.75-3.38 (m, 4H), 2.02-1.69 (m, 4H).MF-DH-23911.5% / 99.59%369.12 for C17H22FN3 O / 370.1 (M + 1)δ 8.41-8.01 (m, 3H), 7.72 (d, J = 8.7 Hz, 2H), 7.12 (d, J = 8.7 Hz, 2H), 3.83 (s, 3H), 3.71-3.33 (m, 4H), 1.68-1.46 (m, 6H).MF-DH-25027.0% / 98.63%437.08 for C20H15ClF 3N3O3 / 438.0 (M + 1)δ 8.47 (d, J = 1.8 Hz, 1H), 8.31 (s, 1H), 8.14 (d, J = 2.0 Hz, 1H), 8.00 (d, J = 2.1 Hz, 1H), 7.74- 7.70 (m, 1H), 7.64-7.61 (m, 1H), 5.02-4.84 (m, 1H), 3.88-3.39 (m, 4H), 2.02-1.69 (m, 4H).MF-DH-25131.6% / 99.67%419.08 for C20H16ClF 2N3O3 / 420.1 (M + 1)δ 8.43 (d, J = 1.8 Hz, 1H), 8.30 (s, 1H), 8.07 (d, J = 1.8 Hz, 1H), 8.00 (d, J = 2.2 Hz, 1H), 7.72 (dd, J = 8.7, 2.1 Hz, 1H), 7.62 (d, J = 8.7 Hz, 1H), 3.69-3.33 (m, 4H), 1.68-1.46 (m, 6H).MF-DH-27342.8% / 99.80%369.12 for C20H20ClN 3O2 / 370.1 (M + 1)δ 8.43 (s, 1H), 8.34 (s, 1H), 8.08- 8.03 (m, 1H), 7.52-7.43 (m, 3H), 7.02-6.95 (m, 1H), 3.84 (s, 3H), 3.68-3.33 (m, 4H), 1.68-1.45 (m, 6H).MF-DH-27457.2% / 99.89%374.07 for C18H16C12 N4O / 375.0 (M + 1)δ 9.18 (d, J = 2.1 Hz, 1H), 8.68- 8.61 (m, 2H), 8.49 (s, 2H), 8.11 (d, J = 1.7 Hz, 1H), 3.71-3.33 (m, 4H), 1.68-1.48 (m, 6H).MF-DH-27543.3% / 99.42%370.12 for C19H19ClN 4O2 / 371.1 (M + 1)δ 8.80-8.79 (m, 1H), 8.47-8.43 (m, 2H), 8.35-8.33 (m, 1H), 8.10- 8.08 (m, 1H), 7.97-7.95 (m, 1H), 3.93 (s, 3H), 3.68-3.57 (m, 1H), 3.33-3.33 (s, 3H), 1.67-1.51 (m, 6H).MF-DH-14611.23% / 99.67%359.09 for C17H15ClF N5O / 360.3 (M + 1)δ 10.00 (s, 1H), 8.66 (s, 2H), 8.50- 8.44 (m, 2H), 6.98 (d, J = 3.8 Hz, 1H), 5.04-4.84 (m, 1H), 3.86- 3.69 (m, 2H), 3.45-3.36 (m, 1H), 3.27-3.19 (m, 1H), 2.06- 1.81 (m, 3H), 1.76-1.63 (m, 1H).MF-DH-1477.5% / 94.04%393.06 for C17H14C12 FN5O / 394.0 (M + 1)δ 9.90 (s, 1H), 8.68 (s, 2H), 8.61 (s, 1H), 8.50 (d, J = 1.6 Hz, 1H), 5.04-4.86 (m, 1H), 3.87-3.73 (m, 2H), 3.43-3.36 (m, 1H), 3.24-3.18 (m, 1H), 2.04-1.84 (m, 3H), 1.75-1.66 (m, 1H).MF-DH-14822.4% / 99.72%339.15 for C18H18FN5 O / 340.1 (M + 1)δ 10.18 (s, 1H), 8.62-8.59 (m, 2H), 8.31 (d, J = 3.8 Hz, 1H), 8.02 (s, 1H), 6.84 (d, J = 3.8 Hz, 1H), 5.02-4.84 (m, 1H), 3.90- 3.65 (m, 2H), 3.41-3.34 (m, 1H), 3.21-3.14 (m, 1H), 2.57-2.56 (m, 3H), 2.05-1.76 (m, 4H).MF-DH-14911.2% / 99.40%373.11 for C18H17ClF N5O / 374.0 (M + 1)δ 10.10 (s, 1H), 8.63 (s, 2H), 8.47-8.45 (m, 1H), 8.05-8.03 (m, 1H), 5.02-4.84 (m, 1H), 3.89-3.66 (m, 2H), 3.37-3.34 (m, 1H), 3.21-3.15 (m, 1H), 2.59 (s, 3H), 2.02-1.68 (m, 4H).MF-PGDH-02013.7% / 99.94%340.11 for C18H17ClN 4O / 341.0 (M + 1)δ 9.11 (s, 1H), 8.51 (d, 1H), 8.30 (d, 1H), 8.20-8.22 (m, 1H), 8.01- 8.03 (m, 1H), 7.70-7.72 (m, 1H), 7.57-7.59 (m, 1H), 3.54-3.67 (m, 2H), 3.34-3.42 (m, 2H), 1.48-1.68 (m, 6H).MF-PGDH-07714.8% / 99.66%336.16 for C19H20N4 O2 / 337.2 (M + 1)δ 8.89 (s, 1H), 8.43 (d, J = 1.83 Hz, 1H), 8.20 (d, J = 1.96 Hz, 1H), 7.78-7.82 (m, 2H), 7.15-7.19 (m, 2H), 3.84 (s, 3H), 3.54-3.68 (m, 2H), 3.34-3.45 (m, 2H), 1.49-1.67 (m, 6H).MF-PGDH-07815% / 99.73%354.15 for C19H19FN4 O2 / 355.2 (M + 1)δ 8.90 (s, 1H), 8.47-8.48 (d, J = 1.83 Hz, 1H), 8.25-8.26 (d, J = 1.96 Hz, 1H), 7.79-7.81 (m, 2H), 7.13-7.15 (m, 2H), 4.82-5.01 (m, 1H), 3.84-3.85 (s, 3H), 3.52- 3.80 (m, 4H), 1.83-2.01 (m, 2H), 1.71-1.82 (m, 2H).MF-PGDH-0795.5% / 98.59%372.14 for C19H18F2N 4O2 / 373.2 (M + 1)δ 8.90 (s, 1H), 8.50-8.51 (d, J = 1.83 Hz, 1H), 8.30-8.31 (d, J = 1.96 Hz, 1H), 7.79-7.81 (m, 2H), 7.16-7.18 (m, 2H), 3.84-3.85 (s, 3H), 3.55-3.70 (m, 4H), 2.03- 2.12 (m, 4H).MF-DH-20118% / 99.77%318.19 for C17H23FN4 O / 319.3 (M + 1)δ 8.65-8.63 (m, 1H), 8.41 (d, J = 1.8 Hz, 1H), 8.14 (d, J = 1.8 Hz, 1H), 5.02-4.83 (m, 1H), 4.51- 4.42 (m, 1H), 3.76-3.45 (m, 4H), 2.11-1.92 (m, 6H), 1.83-1.71 (m, 2H), 0.73-0.68 (m, 6H).MF-DH-21418.7% / 97.08%342.13 for C18H16F2N 4O / 343.1 (M + 1)δ 8.97-8.96 (m, 1H), 8.50-8.48 (m, 1H), 8.29-8.27 (m, 1H), 8.01-7.96 (m, 2H), 7.51-7.46 (m, 2H), 5.03-4.84 (m, 1H), 3.76- 3.48 (m, 4H), 2.02-1.76 (m, 4H).MF-DH-21519% / 98.20%324.14 for C18H17FN4 O / 325.1 (M + 1)δ 8.97-8.95 (m, 1H), 8.46-8.44 (m, 1H), 8.24-8.21 (m, 1H), 8.01- 7.95 (m, 2H), 7.51-7.46 (m, 2H), 3.69-3.38 (m, 4H), 1.67- 1.50 (m, 6H).MF-DH-21619.15% / 99.63%360.12 for C18H15F3N 4O / 361.2 (M + 1)δ 9.03-9.00 (m, 1H), 8.52 (d, J = 1.7 Hz, 1H), 8.30-8.28 (m, 1H), 8.22-8.16 (m, 1H), 7.92-7.87 (m, 1H), 7.77-7.69 (m, 1H), 5.02- 4.84 (m, 1H), 3.76-3.43 (m, 4H), 2.02-1.76 (m, 4H).MF-DH-21720.74% / 98.35%342.13 for C18H16F2N 4O / 343.1 (M + 1)δ 9.02-9.00 (m, 1H), 8.48 (d, J = 1.7 Hz, 1H), 8.24 (d, J = 1.8 Hz, 2H), 7.93-7.87 (m, 1H), 7.78- 7.69 (m, 1H), 3.72-3.52 (m, 2H), 3.49-3.33 (m, 2H), 1.67-1.52 (m, 6H).MF-DH-21812% / 87.77%408.12 for C19H16F4N 4O2 / 409.2 (M + 1)δ 9.04-9.02 (m, 1H), 8.52-8.50 (m, 1H), 8.31-8.29 (m, 1H), 8.13- 8.10 (m, 2H), 7.68-7.64 (m, 2H), 5.04-4.84 (m, 1H), 3.80- 3.54 (m, 4H), 2.00-1.76 (m, 4H).MF-DH-21918% / 97.93%390.13 for C19H17F3N 4O2 / 391.1 (M + 1)δ 9.04-9.00 (m, 1H), 8.48-8.45 (m, 1H), 8.24 (d, J = 1.7 Hz, 1H), 8.11 (brd, J = 8.9 Hz, 2H), 7.65 (brd, J = 8.3 Hz, 2H), 3.75-3.40 (m, 4H), 1.67-1.51 (m, 6H).MF-DH-22214.2% / 99.99%390.13 for C19H17F3N 4O2 / 391.1 (M + 1)δ 8.99-8.98 (m, 1H), 8.50 (d, J = 1.8 Hz, 1H), 8.28 (d, J = 1.8 Hz, 1H), 8.02-7.98 (m, 2H), 7.54- 7.34 (m, 3H), 5.03-4.84 (m, 1H), 3.79-3.47 (m, 4H), 2.04-1.76 (m, 4H).MF-DH-22316.6% / 99.68%372.14 for C19H17F3N 4O2 / 373.1 (M + 1)δ 8.99-8.95 (m, 1H), 8.47-8.44 (m, 1H), 8.22 (d, J = 1.7 Hz, 1H), 8.02-7.99 (m, 1H), 7.54-7.32 (m, 3H), 3.74-3.33 (m, 4H), 1.67-1.49 (m, 6H).MF-DH-22428.5% / 99.38%366.13 for C20H16F2N 4O / 367.2 (M + 1)δ 8.91-8.87 (m, 1H), 8.50-8.44 (m, 1H), 8.25 (d, J = 1.7 Hz, 1H), 7.79 (br d, J = 8.8 Hz, 2H), 7.15 (br d, J = 8.9 Hz, 2H), 5.03-4.84 (m, 1H), 4.16-4.08 (m, 2H), 3.80-3.40 (m, 4H), 2.03-1.89 (m, 2H), 1.83-1.70 (m, 2H), 1.37 (br t, J = 6.9 Hz, 3H).MF-DH-22524.2% / 97.80%350.17 for C20H22N4 O2 / 351.2 (M + 1)δ 8.90-8.85 (m, 1H), 8.43 (d, J = 1.7 Hz, 1H), 8.19 (d, J = 1.7 Hz, 1H), 7.79 (d, J = 8.9 Hz, 2H), 7.15 (d, J = 8.9 Hz, 2H), 4.12 (q, J = 6.9 Hz, 2H), 3.70-3.54 (m, 2H), 3.49-3.34 (m, 2H), 1.67- 1.49 (m, 6H), 1.37 (t, J = 7.0 Hz, 3H).MF-DH-22615.07% / 97.09%408.12 for C19H16F4N 4O2 / 409.1 (M + 1)δ 9.10-9.07 (m, 1H), 8.55-8.52 (m, 1H), 8.32-8.29 (m, 1H), 8.15-8.12 (m, 1H), 8.09 (br d, J = 7.7 Hz, 1H), 7.80-7.74 (m, 1H), 7.53-7.48 (m, 1H), 5.03-4.84 (m, 1H), 3.81-3.40 (m, 4H), 2.03-1.73 (m, 4H).MF-DH-22711.61% / 98.05%390.13 for C19H17F3N 4O2 / 391.1 (M + 1)δ 9.09-9.07 (m, 1H), 8.50-8.48 (m, 1H), 8.26-8.23 (m, 1H), 8.15-8.12 (m, 1H), 8.10-8.06 (m, 1H), 7.80-7.74 (m, 1H), 7.53- 7.47 (m, 1H), 3.78-3.50 (m, 4H), 1.69-1.53 (m, 6H).MF-DH-22829.1% / 98.28%390.13 for C19H17F3N 4O2 / 391.1 (M + 1)δ 9.07-9.04 (m, 1H), 8.53-8.51 (m, 1H), 8.30-8.28 (m, 1H), 7.93-7.88 (m, 2H), 7.71-7.65 (m, 1H), 7.56-7.18 (m, 2H), 5.03-4.84 (m, 1H), 3.80-3.39 (m, 4H), 2.03-1.72 (m, 4H).MF-DH-2295.3% / 95.11%372.14 for C19H18F2N 4O2 / 373.1 (M + 1)δ 9.06-9.03 (m, 1H), 8.48 (d, J = 1.7 Hz, 1H), 8.23 (d, J = 1.7 Hz, 1H), 7.93-7.87 (m, 2H), 7.68 (s, 1H), 7.57-7.17 (m, 2H), 3.70- 3.35 (m, 4H), 1.67-1.51 (m, 6H).MF-DH-23647.3% / 99.81%300.20 for C17H24N4 O / 301.2 (M + 1)δ 8.65-8.62 (m, 1H), 8.37 (d, J = 1.8 Hz, 1H), 8.08 (d, J = 1.7 Hz, 1H), 4.52-4.42 (m, 1H), 3.72- 3.35 (m, 4H), 2.13-1.91 (m, 4H), 1.66-1.49 (m, 6H), 0.73-0.67 (m, 6H).MF-DH-23815% / 99.77%340.13 for C18H17FN4 O2 / 341.2 (M + 1)δ 9.83-9.81 (m, 1H), 8.82 (s, 1H), 8.46 (d, J = 1.7 Hz, 1H), 8.24 (d, J = 1.7 Hz, 1H), 7.64 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 5.03-4.84 (m, 1H), 3.80-3.40 (m, 4H), 2.01-1.75 (m, 4H).MF-DH-44228.77% / 97.51%367.12 for C19H15F2N 5O / 368.2 (M + 1)δ 9.17 (s, 1H), 8.58 (d, J = 1.7 Hz, 1H), 8.38-8.36 (m, 1H), 8.36- 8.28 (m, J = 8.8 Hz, 2H), 8.13 (d, J = 8.7 Hz, 2H), 3.84-3.44 (m, 4H), 2.16-2.01 (m, 4H).MF-DH-44331.25% / 98.35%337.07 for C17H12ClN 5O / 338.1 (M + 1)δ 9.18 (s, 1H), 8.75 (d, J = 1.8 Hz, 1H), 8.46 (d, J = 1.8 Hz, 1H), 8.31 (d, J = 8.8 Hz, 2H), 8.13 (d, J = 8.7 Hz, 2H), 4.89 (br s, 2H), 4.73-4.51 (m, 2H), 4.16 (br s, 1H).MF-DH-46467.3% / 99.47%385.14 for C19H17F2N 5O2 / 386.2 (M + 1)δ 9.10 (s, 1H), 8.56 (d, J = 1.8 Hz, 1H), 8.35 (d, J = 1.8 Hz, 1H), 8.11 (s, 5H), 7.49 (br s, 1H), 3.86-3.42 (m, 4H), 2.17-2.00 (m, 4H).MF-DH-1769.37% / 99.23%368.16 for C20H21FN4 O2 / 369.1 (M + 1)δ 8.29-8.26 (m, 1H), 8.08-8.06 (m, 1H), 7.50-7.45 (m, 2H), 7.17-7.13 (m, 2H), 5.00-4.85 (m, 1H), 3.87-3.84 (m, 3H), 3.80-3.36 (m, 4H), 2.46 (s, 3H), 2.01-1.71 (m, 4H).MF-DH-20520.79% / 99.72%350.17 for C20H22N4 O2 / 351.1 (M + 1)δ 8.25-8.22 (m, 1H), 8.01 (s, 1H), 7.48 (br d, J = 8.7 Hz, 2H), 7.15 (brd, J = 8.8 Hz, 2H), 3.86 (s, 3H), 3.69-3.51 (m, 2H), 3.43-3.34 (m, 2H), 2.46 (br s, 3H), 1.67-1.49 (m, 6H).MF-DH-11728.6% / 97.00%439.20 for C23H26FN5 O3 / 440.1 (M + 1)δ 8.30-8.27 (m, 1H), 8.12 (d, J = 1.7 Hz, 1H), 7.96-7.91 (m, 1H), 7.46 (brd, J = 8.8 Hz, 2H), 7.15 (br d, J = 8.9 Hz, 2H), 5.03-4.84 (m, 1H), 3.89-3.84 (m, 3H), 3.76-3.44 (m, 6H), 2.89 (brt, J = 7.0 Hz, 2H), 2.02-1.85 (m, 2H), 1.80-1.70 (m, 5H).MF-DH-13040% / 98.58%393.16 for C20H22N4 O2 / 391.8 (M-1)δ 8.37-8.35 (m, 1H), 8.24 (d, J = 1.8 Hz, 1H), 7.51 (d, J = 8.9 Hz, 2H), 7.18-7.15 (m, 2H), 5.02- 4.84 (m, 1H), 4.41 (s, 2H), 3.87- 3.85 (m, 3H), 3.78-3.51 (m, 4H), 1.99-1.76 (m, 4H).MF-DH-18427% / 97.46%382.18 for C21H23N3 O2 / 383.1 (M + 1)δ 8.29-8.26 (m, 1H), 8.10 (d, J = 1.7 Hz, 1H), 7.47 (d, J = 8.8 Hz, 2H), 7.15 (d, J = 8.8 Hz, 2H), 5.02-4.83 (m, 1H), 3.86 (s, 3H), 3.74-3.47 (m, 4H), 2.81-2.74 (m, 2H), 2.01-1.75 (m, 4H), 1.28-1.25 (m, 3H).MF-DH-1851.96% / 91.31%412.19 for C22H25FN4 O3 / 413.1 (M + 1)δ 8.32-8.29 (m, 1H), 8.13-8.10 (m, 1H), 7.49-7.44 (m, 2H), 7.18-7.14 (m, 2H), 5.03-4.84 (m, 1H), 3.87-3.85 (m, 3H), 3.73-3.71 (m, 4H), 3.21-3.18 (m, 3H), 3.04-2.99 (m, 2H), 2.01-1.72 (m, 6H).MF-DH-19526% / 99.27%450.17 for C22H22F4N 4O2 / 451.1 (M + 1)δ 8.34-8.30 (m, 1H), 8.15 (s, 1H), 7.50 (br d, J = 8.6 Hz, 2H), 7.17 (brd, J = 8.7 Hz, 2H), 5.02- 4.83 (m, 1H), 3.88-3.85 (m, 3H), 3.74-3.47 (m, 4H), 3.06-3.00 (m, 2H), 2.93-2.79 (m, 2H), 2.02-1.76 (m, 4H).MF-DH-26710% / 93.70%394.20 for C22H26N4 O3 / 395.2 (M + 1)δ 8.26-8.23 (m, 1H), 8.05 (d, J = 1.7 Hz, 1H), 7.46 (d, J = 8.8 Hz, 2H), 7.16 (d, J = 8.8 Hz, 2H), 3.86 (s, 3H), 3.76-3.71 (m, 2H), 3.66-3.44 (m, 3H), 3.19 (s, 3H), 3.04-2.98 (m, 2H), 1.66-1.46 (m, 7H).MF-DH-26822% / 98.27%432.18 for C22H23F3N 4O2 / 433.1 (M + 1)δ 8.28 (s, 1H), 8.09 (s, 1H), 7.56- 7.46 (m, 2H), 7.21-7.11 (m, 2H), 3.86 (s, 3H), 3.72-3.59 (m, 2H), 3.46-3.44 (m, 2H), 3.09- 2.98 (m, 2H), 2.94-2.88 (m, 2H), 1.66-1.46 (m, 6H).MF-DH-33732.7% / 98.99%465.22 for C28H27N5 O2 / 466.1 (M + 1)δ 8.31 (d, J = 1.9 Hz, 1H), 8.21- 8.19 (m, 1H), 8.19-8.09 (m, 2H), 8.00 (d, J = 3.5 Hz, 1H), 7.87 (d, J = 9.0 Hz, 1H), 7.83-7.74 (m, 1H), 7.27-7.22 (m, 2H), 6.91- 6.86 (m, 2H), 6.80-6.77 (m, 1H), 5.65 (s, 2H), 3.70 (s, 3H), 3.64- 3.34 (m, 4H), 1.68-1.45 (m, 6H).MF-DH-34034.2% / 99.35%465.22 for C28H27N5 O2 / 466.2 (M + 1)δ 8.55 (s, 1H), 8.32 (s, 1H), 8.10 (br d, J = 14.5 Hz, 2H), 8.06- 7.93 (m, 1H), 7.76 (br d, J = 9.2 Hz, 1H), 7.72-7.63 (m, 1H), 7.33 (br d, J = 8.4 Hz, 2H), 6.93 (brd, J = 8.4 Hz, 2H), 6.88-6.73 (m, 1H), 5.61 (s, 2H), 3.73 (s, 3H), 3.66-3.37 (m, 4H), 1.69- 1.47 (m, 6H).MF-DH-35121.4% / 99.26%367.14 for C19H18FN5 O2 / 368.2 (M + 1)δ 9.33-9.31 (m, 1H), 9.01 (d, J = 1.6 Hz, 1H), 8.76-8.73 (m, 1H), 8.43 (d, J = 2.0 Hz, 1H), 8.28 (br s, 1H), 8.23-8.19 (m, 2H), 7.76 (br s, 1H), 6.91-6.88 (m, 1H), 5.03-4.84 (m, 1H), 3.76-3.56 (m, 4H), 1.99-1.75 (m, 4H).MF-DH-35538.7% / 90.57%367.14 for C19H18FN5 O2 / 368.2 (M + 1)δ 9.27 (d, J = 2.4 Hz, 1H), 8.64- 8.59 (m, 1H), 8.44 (d, J = 2.0 Hz, 1H), 8.32-8.20 (m, 3H), 8.20- 8.05 (m, 1H), 7.70 (br s, 1H), 6.91 (d, J = 3.8 Hz, 1H), 5.03- 4.84 (m, 1H), 3.79-3.46 (m, 4H), 2.03-1.74 (m, 4H).MF-DH-36153.1% / 99.56%349.15 for C19H19N5 O2 / 350.2 (M + 1)δ 9.32 (d, J = 2.4 Hz, 1H), 9.00 (d, J = 1.7 Hz, 1H), 8.74 (t, J = 2.2 Hz, 1H), 8.39 (d, J = 2.0 Hz, 1H), 8.27 (br s, 1H), 8.22-8.15 (m, 2H), 7.78-7.73 (m, 1H), 6.89 (d, J = 3.8 Hz, 1H), 3.71-3.37 (m, 4H), 1.68-1.50 (m, 6H).MF-DH-36246.6% / 95.07%363.17 for C20H21N5 O2 / 364.2 (M + 1)δ 9.32-9.29 (m, 1H), 8.96 (d, J = 1.9 Hz, 1H), 8.75 (br d, J = 4.6 Hz, 1H), 8.72 (t, J = 2.2 Hz, 1H), 8.40-8.38 (m, 1H), 8.20- 8.15 (m, 2H), 6.90-6.87 (m, 1H), 3.70-3.44 (m, 4H), 2.87- 2.83 (m, 3H), 1.67-1.61 (m, 2H), 1.60-1.48 (m, 4H).MF-DH-36334.2% / 98.79%377.19 for C21H23N5 O2 / 378.2 (M + 1)δ 9.33-9.18 (m, 1H), 8.60 (s, 1H), 8.48 (br s, 1H), 8.43-8.34 (m, 1H), 8.26-8.12 (m, 2H), 6.87 (br d, J = 3.4 Hz, 1H), 3.76- 3.37 (m, 4H), 3.09-2.97 (m, 6H), 1.67-1.44 (m, 6H).MF-DH-36432.7% / 97.33%331.14 for C19H17N5 O / 332.2 (M + 1)δ 9.58-9.55 (m, 1H), 9.01-8.95 (m, 2H), 8.43-8.39 (m, 1H), 8.25-8.14 (m, 2H), 6.93-6.89 (m, 1H), 3.68-3.34 (m, 4H), 1.68-1.50 (m, 6H).MF-DH-36551.5% / 96.50%349.15 for C19H19N5 O2 / 350.2 (M + 1)δ 9.27 (br s, 1H), 8.62 (br d, J = 7.1 Hz, 1H), 8.40 (br s, 1H), 8.29-8.10 (m, 4H), 7.69 (br s, 1H), 6.90 (brd, J = 3.1 Hz, 1H), 3.73-3.40 (m, 4H), 1.68-1.50 (m, 6H).MF-DH-36644.7% / 99.68%349.19 for C20H23N5 O / 350.2 (M + 1)δ 8.43 (d, J = 2.4 Hz, 1H), 8.29 (d, J = 2.0 Hz, 1H), 8.10 (d, J = 2.0 Hz, 1H), 7.92-7.86 (m, 2H), 6.82-6.73 (m, 2H), 3.69-3.34 (m, 4H), 3.09 (s, 6H), 1.67-1.49 (m, 6H).MF-DH-37612.5% / 99.64%348.20 for C21H24N4 O / 349.2 (M + 1)δ 8.34-8.32 (m, 1H), 8.12 (d, J = 2.0 Hz, 1H), 8.00 (d, J = 3.7 Hz, 1H), 7.82-7.72 (m, 2H), 7.48 (t, J = 7.8 Hz, 1H), 7.39 (d, J = 7.7 Hz, 1H), 6.79 (d, J = 3.7 Hz, 1H), 4.13-4.06 (m, 1H), 3.79- 3.33 (m, 6H), 1.68-1.51 (m, 6H), 1.36-1.30 (m, 3H).MF-DH-38038.2% / 99.26%380.16 for C21H21FN4 O2 / 381.2 (M + 1)δ 8.19 (s, 1H), 8.13-7.99 (m, 6H), 7.41 (brs, 1H), 6.94-6.91 (m, 1H), 5.01-4.82 (m, 1H), 3.88-3.65 (m, 2H), 3.41-3.33 (m, 1H), 3.22-3.13 (m, 1H), 2.52 (br s, 3H), 2.06-1.57 (m, 4H).MF-DH-38270.1% / 99.58%400.11 for C20H18ClF N4O2 / 401.2 (M + 1)δ 8.51-8.42 (m, 2H), 8.13 (s, 1H), 8.10-8.01 (m, 5H), 7.42 (s, 1H), 5.01-4.80 (m, 1H), 3.81- 3.40 (m, 4H), 2.03-1.72 (m, 4H).MF-DH-38339.5% / 97.76%382.12 for C20H19ClN 4O2 / 383.1 (M + 1)δ 8.47-8.45 (m, 1H), 8.43-8.41 (m, 1H), 8.09-8.03 (m, 6H), 7.46-7.42 (m, 1H), 3.72-3.40 (m, 4H), 1.67-1.52 (m, 6H).MF-DH-38550.6% / 99.68%440.22 for C27H28N4 O2 / 441.3 (M + 1)δ 7.77 (br s, 1H), 7.65 (d, J = 8.9 Hz, 2H), 7.45 (d, J = 3.8 Hz, 1H), 7.37-7.30 (m, 4H), 7.30- 7.17 (m, 1H), 7.11-7.00 (m, 3H), 6.72 (d, J = 3.7 Hz, 1H), 4.76 (d, J = 6.5 Hz, 2H), 3.80 (s, 3H), 3.38 (br s, 4H), 1.60-1.42 (m, 6H).MF-DH-38738.4% / 99.79%362.15 for C21H19FN4 O / 363.2 (M + 1)δ 8.29 (d, J = 8.8 Hz, 2H), 8.23- 8.15 (m, 2H), 8.03 (d, J = 8.7 Hz, 2H), 6.98 (d, J = 3.9 Hz, 1H), 5.02-4.82 (m, 1H), 3.88-3.64 (m, 2H), 3.40-3.33 (m, 1H), 3.22-3.12 (m, 1H), 2.56-2.51 (m, 3H), 2.06-1.58 (m, 4H).MF-DH-38816.66% / 99.83%382.10 for C20H16ClF N4O / 383.2 (M + 1)δ 8.50-8.46 (m, 2H), 8.24-8.20 (m, 2H), 8.1-8.12 (m, 1H), 8.05- 8.01 (m, 2H), 4.99-4.80 (m, 1H), 3.89-3.43 (m, 4H), 1.99- 1.65 (m, 4H).MF-DH-3926.84% / 95.06%335.17 for C19H21N5 O / 336.2 (M + 1)δ 8.30-8.27 (m, 1H), 8.08 (d, J = 1.9 Hz, 2H), 7.82 (d, J = 3.5 Hz, 1H), 7.64 (d, J = 1.9 Hz, 1H), 6.73-6.71 (m, 1H), 5.94 (s, 2H), 3.60-3.43 (m, 4H), 2.13 (s, 3H), 1.65-1.52 (m, 6H).MF-DH-39316.5% / 98.32%355.12 for C18H18ClN 5O / 356.2 (M + 1)δ 8.33-8.30 (m, 2H), 8.10 (d, J = 2.1 Hz, 2H), 7.93-7.91 (m, 1H), 6.76-6.74 (m, 1H), 6.52 (s, 2H), 3.55-3.39 (m, 4H), 1.67-1.53 (m, 6H).MF-DH-395 (Cis-relative)13.7% / 99.97%376.19 for C22H24N4 O2 / 377.2 (M + 1)δ 8.33 (d, J = 1.9 Hz, 1H), 8.14- 8.10 (m, 2H), 8.10-8.02 (m, 5H), 7.44-7.38 (m, 1H), 6.82 (d, J = 3.8 Hz, 1H), 4.48-4.27 (m, 2H), 1.92-1.78 (m, 1H), 1.72-1.61 (m, 2H), 1.59-1.44 (m, 3H), 1.29-1.17 (m, 6H).MF-DH-39668.1% / 99.29%381.14 for C20H17F2N 5O / 382.2 (M + 1)δ 13.26 (brs, 1H), 8.41-8.40 (m, 1H), 8.22 (d, J = 2.1 Hz, 1H), 8.20-8.18 (m, 1H), 8.16-8.14 (m, 1H), 8.04-8.02 (m, 1H), 7.80-7.77 (m, 1H), 7.73-7.70 (m, 1H), 6.80 (d, J = 3.6 Hz, 1H), 3.72-3.59 (m, 4H), 2.12-2.04 (m, 4H).MF-DH-39768.9% / 99.77%332.14 for C18H16N6 O / 333.2 (M + 1)δ 9.82 (s, 2H), 8.45 (d, J = 1.9 Hz, 1H), 8.36 (d, J = 3.9 Hz, 1H), 8.21 (d, J = 1.9 Hz, 1H), 7.00 (d, J = 3.9 Hz, 1H), 3.74-3.33 (m, 4H), 1.68-1.46 (m, 6H).MF-DH-39936.05% / 95.01%363.17 for C20H21N5 O2 / 364.2 (M + 1)δ 9.70 (s, 1H), 8.36 (d, J = 1.8 Hz, 1H), 8.13 (d, J = 1.8 Hz, 1H), 8.12-8.04 (m, 1H), 7.99-7.90 (m, J = 8.7 Hz, 2H), 7.89-7.82 (m, 2H), 6.81 (d, J = 3.7 Hz, 1H), 5.89 (s, 2H), 3.68-3.37 (m, 4H), 1.68-1.50 (m, 6H).MF-DH-40019.2% / 92.70%363.17 for C20H21N5 O2 / 364.2 (M + 1)δ 9.75 (s, 1H), 8.34 (d, J = 2.0 Hz, 1H), 8.14-8.06 (m, 3H), 7.96- 7.84 (m, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.60-7.52 (m, 1H), 6.81 (d, J = 3.8 Hz, 1H), 5.93 (s, 2H), 3.75-3.40 (m, 4H), 1.69-1.51 (m, 6H).MF-DH-40231.2% / 99.68%387.17 for C22H21N5 O2 / 388.3 (M + 1)δ 8.22-8.18 (m, 1H), 8.00-7.99 (m, 1H), 7.85-7.79 (m, 2H), 7.48-7.43 (m, 1H), 7.26-7.23 (m, 1H), 7.11-7.04 (m, 2H), 3.90 (s, 3H), 3.87-3.62 (m, 2H), 3.37 (br s, 2H), 1.71 (br s, 6H).MF-DH-40345.4% / 98.95%511.24 for C27H31F2N 5O3 / 512.3 (M + 1)δ 8.62-8.55 (m, 1H), 8.55-8.44 (m, 1H), 8.23 (d, J = 2.0 Hz, 1H), 8.16 (d, J = 3.6 Hz, 1H), 8.11- 7.98 (m, 4H), 7.62 (s, 1H), 6.85 (d, J = 3.8 Hz, 1H), 3.79-3.51 (m, 4H), 3.40-3.36 (m, 2H), 3.29-3.23 (m, 2H), 2.14-2.02 (m, 4H), 1.09 (s, 9H).MF-DH-40418.1% / 99.02%426.19 for C23H24F2N 4O2 / 427.2 (M + 1)δ 8.45 (d, J = 2.0 Hz, 1H), 8.30- 8.27 (m, 1H), 8.24-8.22 (m, 1H), 8.22-8.11 (m, 1H), 8.10-7.99 (m, 4H), 6.85 (d, J = 3.8 Hz, 1H), 4.18-4.08 (m, 1H), 3.76-3.50 (m, 4H), 2.15-2.01 (m, 4H), 1.21-1.18 (m, 6H).MF-DH-40535.32% / 99.98%455.21 for C24H27F2N 5O2 / 456.3 (M + 1)δ 9.32-9.30 (m, 1H), 8.99 (d, J = 1.9 Hz, 1H), 8.72 (t, J = 2.3 Hz, 1H), 8.68-8.60 (m, 1H), 8.47 (d, J = 2.0 Hz, 1H), 8.26 (d, J = 2.0 Hz, 1H), 8.23-8.21 (m, 1H), 6.91-6.89 (m, 1H), 3.75-3.56 (m, 4H), 3.19-3.15 (m, 2H), 2.16-2.02 (m, 4H), 0.94 (s, 9H).MF-DH-40638.9% / 93.87%441.20 for C23H25F2N 5O2 / 442.2 (M + 1)δ 9.28-9.26 (m, 1H), 8.65-8.61 (m, 1H), 8.48-8.46 (m, 1H), 8.27-8.19 (m, 3H), 8.05 (s, 1H), 6.93-6.91 (m, 1H), 3.81-3.53 (m, 4H), 2.16- 2.01 (m, 4H), 1.44 (s, 9H).MF-DH-40729.2% / 97.29%455.21 for C24H27F2N 5O2 / 456.3 (M + 1)δ 9.32-9.29 (m, 1H), 9.00 (d, J = 1.5 Hz, 1H), 8.71 (s, 1H), 8.47 (d, J = 1.8 Hz, 1H), 8.39-8.19 (m, 3H), 6.90 (d, J = 3.7 Hz, 1H), 3.89-3.79 (m, 1H), 3.76-3.52 (m, 4H), 2.17-2.01 (m, 4H), 1.65-1.47 (m, 4H), 0.92-0.87 (m, 6H).MF-DH-40918.3% / 95.45%505.16 for C23H25F2N 5O4S / 506.2 (M + 1)δ 8.64-8.58 (m, 1H), 8.47-8.44 (m, 1H), 8.23 (d, J = 2.0 Hz, 1H), 8.17-8.14 (m, 1H), 8.12-8.02 (m, 4H), 7.20-7.15 (m, 1H), 6.87-6.84 (m, 1H), 3.78-3.52 (m, 4H), 3.45-3.38 (m, 2H), 3.19-3.12 (m, 2H), 2.92 (s, 3H), 2.14-2.02 (m, 4H).MF-DH-41149.6% / 98.58%427.18 for C22H23F2N 5O2 / 428.2 (M + 1)1H NMR (CD3OD): δ 8.46-8.43 (m, 1H), 8.21 (d, J = 1.9 Hz, 1H), 8.11-7.99 (m, 4H), 7.93 (d, J = 3.8 Hz, 1H), 6.85 (d, J = 3.8 Hz, 1H), 3.93-3.68 (m, 4H), 3.65- 3.59 (m, 2H), 3.11-3.04 (m, 2H), 2.17-2.02 (m, 4H).MF-DH-41225.3% / 99.18%458.18 for C23H24F2N 4O4 / 459.2 (M + 1)δ 8.46 (d, J = 2.1 Hz, 1H), 8.23 (d, J = 2.0 Hz, 1H), 8.15 (d, J = 3.7 Hz, 1H), 8.10-8.03 (m, 5H), 6.86 (d, J = 3.8 Hz, 1H), 4.68 (t, J = 5.7 Hz, 2H), 4.03-3.96 (m, 1H), 3.83-3.58 (m, 4H), 3.58- 3.52 (m, 4H), 2.08 (br s, 4H).MF-DH-41318.1% / 95.26%428.17 for C22H22F2N 4O3 / 429.2 (M + 1)δ 8.56-8.50 (m, 1H), 8.47-8.44 (m, 1H), 8.25-8.21 (m, 1H), 8.17-8.13 (m, 1H), 8.10-8.02 (m, 4H), 6.87-6.83 (m, 1H), 4.78-4.73 (m, 1H), 3.71-3.52 (m, 6H), 3.40-3.37 (m, 2H), 2.15-2.03 (m, 4H).MF-DH-417 (Cis-relative)54.34% / 99.38%366.13 for C20H16F2N 4O / 367.2 (M + 1)δ 8.43-8.38 (m, 1H), 8.30 (br d, J = 8.4 Hz, 2H), 8.25-8.19 (m, 1H), 8.19-8.12 (m, 1H), 8.05 (br d, J = 8.4 Hz, 2H), 6.91 (br d, J = 3.4 Hz, 1H), 5.08-4.63 (m, 3H), 4.13-3.84 (m, 1H), 2.70-2.66 (m, 1H), 2.36-2.22 (m, 2H), 2.18-1.98 (m, 1H).MF-DH-41848.5% / 97.93%412.17 for C22H22F2N 4O2 / 413.2 (M + 1)δ 8.56-8.51 (m, 1H), 8.45 (d, J = 2.0 Hz, 1H), 8.23 (d, J = 2.1 Hz, 1H), 8.14 (d, J = 3.8 Hz, 1H), 8.10-7.99 (m, 4H), 6.85 (d, J = 3.8 Hz, 1H), 3.80-3.52 (m, 4H), 3.36-3.32 (m, 2H), 2.14-2.00 (m, 4H), 1.18-1.13 (m, 3H).MF-DH-41919.7% / 99.55%467.21 for C25H27F2N 5O2 / 468.3 (M + 1)δ 8.47-8.43 (m, 1H), 8.37 (br d, J = 7.7 Hz, 1H), 8.25-8.21 (m, 1H), 8.17-8.12 (m, 1H), 8.09- 8.01 (m, 4H), 6.87-6.83 (m, 1H), 3.99-3.87 (m, 1H), 3.82-3.53 (m, 4H), 3.44-3.38 (m, 1H), 3.09 (br d, J = 12.1 Hz, 2H), 2.67 (br d, J = 5.3 Hz, 2H), 2.14-2.03 (m, 4H), 1.88-1.80 (m, 2H), 1.58- 1.49 (m, 2H).MF-DH-4208.5% / 98.08%439.18 for C23H23F2N 5O2 / 440.0 (M + 1)δ 8.93-8.86 (m, 1H), 8.45 (d, J = 2.0 Hz, 1H), 8.23 (d, J = 2.0 Hz, 1H), 8.15 (s, 1H), 8.06 (d, J = 4.0 Hz, 4H), 6.86 (d, J = 3.8 Hz, 1H), 4.78-4.68 (m, 1H), 3.82- 3.44 (m, 8H), 2.15-2.01 (m, 4H).MF-DH-42113.7% / 97.62%516.16 for C25H26F2N 4O4S / 516.9δ 8.51-8.47 (m, 1H), 8.46-8.44 (m, 1H), 8.25-8.22 (m, 1H), 8.16-8.13 (m, 1H), 8.10-8.03 (m, 4H), 6.88-6.84 (m, 1H), 4.28-4.20 (m, 1H), 3.84-3.37 (m, 6H), 3.20-3.09 (m, 2H), 2.20-2.04 (m, 8H).MF-DH-42246.72% / 93.38%413.17 for C21H21F2N 5O2 / 414.2 (M + 1)δ 9.28-9.26 (m, 1H), 8.85-8.80 (m, 1H), 8.64-8.59 (m, 1H), 8.49-8.45 (m, 1H), 8.28-8.19 (m, 3H), 6.93-6.90 (m, 1H), 3.80-3.52 (m, 4H), 3.41-3.34 (m, 2H), 2.15-2.01 (m, 4H), 1.19-1.13 (m, 3H).MF-DH-42656.5% / 90.34%399.14 for C21H19F2N 3O3 / 400.0 (M + 1)δ 12.48-12.15 (m, 1H), 8.42- 8.39 (m, 1H), 8.21 (d, J = 2.0 Hz, 1H), 8.02 (d, J = 3.7 Hz, 1H), 7.82 (d, J = 8.6 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 6.80 (d, J = 3.7 Hz, 1H), 3.78-3.51 (m, 6H), 2.15-1.98 (m, 4H).MF-DH-42731.3% / 98.54%425.16 for C23H21F2N 3O3 / 426.0 (M + 1)δ 12.55-12.22 (m, 1H), 8.40 (d, J = 2.1 Hz, 1H), 8.21 (d, J = 2.0 Hz, 1H), 8.02 (d, J = 3.7 Hz, 1H), 7.79 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.6 Hz, 2H), 6.80 (d, J = 3.5 Hz, 1H), 3.73-3.54 (m, 4H), 2.14-2.01 (m, 4H), 1.50 (br d, J = 2.9 Hz, 2H), 1.26-1.17 (m, 2H).MF-DH-42821.3% / 98.9%462.12 for C21H20F2N 4O4S / 463.2 (M + 1)δ 12.27-12.14 (m, 1H), 8.48 (d, J = 2.0 Hz, 1H), 8.26-8.19 (m, 4H), 8.17-8.12 (m, 2H), 6.88 (d, J = 3.8 Hz, 1H), 3.80-3.53 (m, 4H), 3.42-3.40 (m, 3H), 2.08 (br s, 4H).MF-DH-42927.6% / 98.97%468.16 for C24H22F2N 4O4 / 469.0 (M + 1)δ 12.43-12.28 (m, 1H), 9.07- 8.99 (m, 1H), 8.48-8.43 (m, 1H), 8.24-8.21 (m, 1H), 8.18-8.13 (m, 1H), 8.12-8.07 (m, 2H), 8.06-8.01 (m, 2H), 6.88-6.82 (m, 1H), 3.75-3.53 (m, 4H), 2.15-1.99 (m, 4H), 1.46-1.40 (m, 2H), 1.17-1.10 (m, 2H).MF-DH-43030.1% / 98.97%468.16 for C24H22F2N 4O4 / 469.0 (M + 1)δ 12.43-12.28 (m, 1H), 9.07- 8.99 (m, 1H), 8.48-8.43 (m, 1H), 8.24-8.21 (m, 1H), 8.18-8.13 (m, 1H), 8.12-8.07 (m, 2H), 8.06-8.01 (m, 2H), 6.88-6.82 (m, 1H), 3.75-3.53 (m, 4H), 2.15-1.99 (m, 4H), 1.46-1.40 (m, 2H), 1.17-1.10 (m, 2H).MF-DH-4314.9% / 95.80%484.19 for C25H26F2N 4O4 / 455.2 (M + 1)δ 12.12-11.99 (m, 1H), 8.46- 8.44 (m, 1H), 8.24-8.22 (m, 1H), 8.15-8.12 (m, 1H), 8.06-8.02 (m, 2H), 7.98-7.91 (m, 3H), 6.85 (d, J = 3.7 Hz, 1H), 3.77-3.54 (m, 4H), 2.84-2.80 (m, 2H), 2.15-2.03 (m, 4H), 1.49-1.45 (m, 6H).MF-DH-4326.8% / 99.48%482.18 for C25H24F2N 4O4 / 483.2 (M + 1)δ = 8.45 (d, J = 2.0 Hz, 1H), 8.23 (d, J = 2.0 Hz, 1H), 8.13 (d, J = 3.8 Hz, 1H), 8.05 (d, J = 8.6 Hz, 2H), 7.73 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 3.5 Hz, 1H), 4.50- 4.42 (m, 1H), 3.75-3.57 (m, 6H), 2.36-2.26 (m, 1H), 2.15-2.00 (m, 4H), 1.97-1.80 (m, 3H).MF-DH-43378.1% / 99.82%349.14 for C20H19N3 O3 / 350.1 (M + 1)δ 13.08-12.95 (m, 1H), 8.38 (d, J = 2.0 Hz, 1H), 8.18-8.09 (m, 6H), 6.86 (d, J = 3.8 Hz, 1H), 3.76-3.40 (m, 4H), 1.69-1.50 (m, 6H)MF-DH-43453.2% / 94.01%386.12 for C19H16F2N 4O3 / 387.1 (M + 1)δ 13.73-12.61 (m, 1H), 9.36- 9.34 (m, 1H), 8.66 (dd, J = 8.5, 2.5 Hz, 1H), 8.49 (d, J = 1.9 Hz, 1H), 8.30-8.22 (m, 3H), 6.93 (d, J = 3.8 Hz, 1H), 3.76-3.50 (m, 4H), 2.15-2.01 (m, 4H).MF-DH-43761.3% / 94.05%455.21 for C24H27F2N 5O2 / 456.2 (M + 1)δ 9.28-9.25 (m, 1H), 8.63-8.59 (m, 1H), 8.48-8.46 (m, 1H), 8.37-8.31 (m, 1H), 8.28-8.20 (m, 3H), 6.93-6.89 (m, 1H), 3.87-3.78 (m, 1H), 3.75-3.48 (m, 4H), 2.16-2.02 (m, 4H), 1.65-1.55 (m, 4H), 0.87 (t, J = 7.4 Hz, 6H).MF-DH-43842.7% / 95.24%455.21 for C24H27F2N 5O2 / 456.2 (M + 1)δ 9.31-9.27 (m, 1H), 8.66-8.55 (m, 2H), 8.47 (d, J = 1.9 Hz, 1H), 8.28-8.21 (m, 3H), 6.93-6.91 (m, 1H), 3.81-3.44 (m, 4H), 3.19 (d, J = 6.6 Hz, 2H), 2.15-2.01 (m, 4H), 0.93 (s, 9H).MF-DH-43941.6% / 95.51%366.13 for C20H16F2N 4O / 367.1 (M + 1)δ 8.48-8.46 (m, 1H), 8.32-8.27 (m, 2H), 8.26-8.21 (m, 2H), 8.07-8.03 (m, 2H), 6.91-6.88 (m, 1H), 3.77-3.48 (m, 4H), 2.15-2.02 (m, 4H).MF-DH-44037.5% / 98.38%367.12 for C19H15F2N 5O / 368.1 (M + 1)δ 9.17 (d, J = 8.8 Hz, 1H), 9.01 (d, J = 1.6 Hz, 1H), 8.57-8.50 (m, 3H), 8.28 (d, J = 2.0 Hz, 1H), 6.94 (d, J = 3.9 Hz, 1H), 3.81- 3.38 (m, 4H), 2.15-2.02 (m, 4HMF-DH-44132.4% / 96.34%382.12 for C20H16F2N 4O2 / 383.1 (M + 1)δ 9.44-9.41 (m, 1H), 9.27-9.23 (m, 1H), 9.15-9.10 (m, 1H), 8.58-8.55 (m, 1H), 8.35-8.32 (m, 2H), 7.01-6.98 (m, 1H), 3.79-3.67 (m, 4H), 2.22-2.12 (m, 4H).MF-DH-44228.7% / 97.51%367.12 for C19H15F2N 5O / 368.2 (M + 1)δ 9.17 (s, 1H), 8.58 (d, J = 1.7 Hz, 1H), 8.38-8.36 (m, 1H), 8.36- 8.28 (m, J = 8.8 Hz, 2H), 8.13 (d, J = 8.7 Hz, 2H), 3.84-3.44 (m, 4H), 2.16-2.01 (m, 4H).MF-DH-44331.2% / 98.35%337.07 for C17H12ClN 5O / 338.1 (M + 1)δ 9.18 (s, 1H), 8.75 (d, J = 1.8 Hz, 1H), 8.46 (d, J = 1.8 Hz, 1H), 8.31 (d, J = 8.8 Hz, 2H), 8.13 (d, J = 8.7 Hz, 2H), 4.89 (br s, 2H), 4.73-4.51 (m, 2H), 4.16 (br s, 1H).MF-DH-4447.2% / 99.93%452.2 for C21H19F2N 3O2 / 453.2 (M + 1)δ 8.24-8.20 (m, 1H), 8.11-8.04 (m, 3H), 7.75 (d, J = 8.5 Hz, 2H), 6.60-6.56 (m, 1H), 4.24-4.21 (m, 1H), 3.73-3.52 (m, 4H), 2.79-2.71 (m, 2H), 2.13-2.00 (m, 4H), 1.68-1.58 (m, 2H), 1.04- 1.01 (m, 6H).MF-DH-4463.5% / 91.47%437.17 for C23H21F2N 5O2 / 438.2 (M + 1)δ 8.24-8.22 (m, 1H), 8.11-8.07 (m, 3H), 7.78-7.73 (m, 2H), 7.39-7.35 (m, 1H), 6.85-6.81 (m, 1H), 6.58-6.56 (m, 1H), 3.73-3.54 (m, 4H), 2.92-2.89 (m, 2H), 2.69-2.66 (m, 2H), 2.11-2.00 (m, 4H).MF-DH-44835.1% / 97.53%441.20 for C23H25F2N 5O2 / 442.2 (M + 1)δ 9.30-9.27 (m, 1H), 8.96-8.92 (m, 1H), 8.65 (s, 1H), 8.50-8.44 (m, 1H), 8.28-8.20 (m, 2H), 8.15- 8.10 (m, 1H), 6.92-6.87 (m, 1H), 3.77-3.58 (m, 4H), 2.16- 2.02 (m, 4H), 1.45-1.40 (s, 9H).MF-DH-44912.8% / 94.14%382.11 for C20H16F2N 4S / 383.1 (M + 1)δ 8.41-8.38 (m, 1H), 8.31-8.26 (m, 2H), 8.22-8.19 (m, 1H), 8.16- 8.13 (m, 1H), 8.08-8.02 (m, 2H), 6.89-6.86 (m, 1H), 4.49- 4.43 (m, 2H), 3.76-3.70 (m, 2H), 2.31-2.21 (m, 2H), 2.18-2.08 (m, 2H).MF-DH-45031.3% / 92.56%481.19 for C25H25F2N 5O3 / 482.0 (M + 1)δ 8.46-8.43 (m, 1H), 8.25-8.21 (m, 1H), 8.16-8.10 (m, 1H), 8.06- 7.99 (m, 2H), 7.81-7.74 (m, 2H), 7.59-7.40 (m, 1H), 7.00- 6.94 (m, 1H), 6.87-6.82 (m, 1H), 4.43-4.27 (m, 1H), 3.75-3.45 (m, 6H), 2.25-2.03 (m, 5H), 1.97-1.77 (m, 3H).MF-DH-45132.78% / 95.52%472.19 for C24H26F2N 4O4 / 473.0 (M + 1)δ 8.48-8.42 (m, 1H), 8.27-8.20 (m, 1H), 8.13-8.09 (m, 1H), 8.01- 7.96 (m, 2H), 7.62-7.58 (m, 2H), 6.86-6.82 (m, 1H), 3.60- 3.36 (m, 14H), 2.15-2.01 (m, 4H).MF-DH-45245.3% / 94.26%410.14 for C19H16F2N 8O / 411.1 (M + 1)δ 9.41-8.99 (m, 1H), 8.62-8.57 (m, 1H), 8.41-8.32 (m, 2H), 8.27- 8.24 (m, 1H), 8.18-8.12 (m, 1H), 6.94-6.88 (m, 1H), 3.81- 3.50 (m, 4H), 2.13-2.03 (m, 4H).MF-DH-45332.6% / 98.39%410.14 for C19H16F2N 8O / 409.2 (M-1)δ 9.44-9.41 (m, 1H), 9.25 (d, J = 1.3 Hz, 1H), 9.14-9.12 (m, 1H), 8.58-8.55 (m, 1H), 8.36-8.32 (m, 2H), 7.01-6.98 (m, 1H), 3.80- 3.68 (m, 4H), 2.21-2.12 (m, 4H).MF-DH-45413.3% / 94.20%426.13 for C20H16F2N 6O3 / 425.2 (M − 1)δ 9.33-9.29 (m, 1H), 8.96-8.92 (m, 1H), 8.82-8.78 (m, 1H), 8.50- 8.46 (m, 1H), 8.28-8.21 (m, 2H), 6.92-6.89 (m, 1H), 3.75- 3.57 (m, 4H), 2.15-2.05 (m, 4H).MF-DH-4555.8% / 91.76%409.15 for C20H17F2N 7O / 410.2 (M + 1)δ 9.32-9.28 (m, 1H), 8.65-8.59 (m, 1H), 8.52-8.47 (m, 1H), 8.32- 8.25 (m, 4H), 6.95-6.90 (m, 1H), 3.84-3.51 (m, 4H), 2.17- 2.06 (m, 4H).MF-DH-45637.7% / 92.01%426.13 for C20H16F2N 6O3 / 427.12 (M + 1)δ 13.29-13.14 (m, 1H), 9.42 (d, J = 2.1 Hz, 1H), 8.78-8.71 (m, 1H), 8.49 (d, J = 1.7 Hz, 1H), 8.33-8.24 (m, 2H), 8.24-8.17 (m, 1H), 6.94 (d, J = 3.7 Hz, 1H), 3.82-3.55 (m, 4H), 2.08 (br d, J = 3.5 Hz, 4H).MF-DH-45719.1% / 97.36%468.17 for C23H22F2N 6O3 / 469.3 (M + 1)δ 8.97-8.92 (m, 1H), 8.72-8.69 (m, 1H), 8.61-8.57 (m, 1H), 8.54- 8.47 (m, 2H), 8.29-8.24 (m, 1H), 8.15-8.10 (m, 1H), 6.90- 6.86 (m, 1H), 3.79-3.54 (m, 4H), 2.15-2.04 (m, 4H), 1.45 (s, 6H).MF-DH-45823.8% / 99.36%452.14 for C22H18F2N 6O3 / 453.2 (M + 1)δ 11.25-11.22 (m, 1H), 8.98 (d, J = 2.2 Hz, 1H), 8.92-8.89 (m, 1H), 8.87-8.84 (m, 2H), 8.47- 8.45 (m, 1H), 8.27-8.24 (m, 1H), 8.15-8.12 (m, 1H), 7.35-7.32 (m, 1H), 6.90-6.87 (m, 1H), 3.74- 3.45 (m, 4H), 2.14-2.02 (m, 4H).MF-DH-45939.3% / 99.82%452.14 for C22H18F2N 6O3 / 451.2 (M − 1)δ 12.42-12.37 (m, 1H), 9.47 (d, J = 2.4 Hz, 1H), 9.14-9.12 (m, 1H), 8.93 (t, J = 2.1 Hz, 1H), 8.56 (d, J = 1.8 Hz, 1H), 8.49 (d, J = 1.8 Hz, 1H), 8.29-8.24 (m, 2H), 6.93 (d, J = 3.7 Hz, 1H), 6.50 (d, J = 1.8 Hz, 1H), 3.81-3.48 (m, 4H), 2.12-2.02 (m, 4H).MF-DH-4608.5% / 95.03%452.14 for C22H18F2N 6O3 / 453.2 (M + 1)δ 12.23-12.19 (m, 1H), 9.45- 9.42 (m, 1H), 8.77-8.72 (m, 1H), 8.55-8.53 (m, 1H), 8.51-8.49 (m, 1H), 8.38-8.34 (m, 1H), 8.33- 8.31 (m, 1H), 8.29-8.27 (m, 1H), 6.96-6.94 (m, 1H), 6.50- 6.47 (m, 1H), 3.79-3.56 (m, 4H), 2.16-2.04 (m, 4H).MF-DH-46238.5% / 99.52%348.14 for C20H17FN4 O / 349.1 (M + 1)δ 8.24-8.15 (m, 2H), 8.10-8.06 (m, 2H), 7.93-7.88 (m, 2H), 7.49- 7.46 (m, 1H), 6.97-6.94 (m, 1H), 5.03-4.85 (m, 1H), 3.79- 3.44 (m, 4H), 2.06-1.67 (m, 4H).MF-DH-46342.1% / 99.89%348.14 for C20H17FN4 O / 349.0 (M + 1)δ 8.98 (s, 1H), 8.15-8.05 (m, 3H), 8.01-7.92 (m, 3H), 6.95 (d, J = 3.1 Hz, 1H), 5.03-4.84 (m, 1H), 3.78-3.43 (m, 4H), 2.01- 1.66 (m, 4H).MF-DH-46446.5% / 99.47%385.14 for C19H17F2N 5O2 / 386.2 (M + 1)δ 9.10 (s, 1H), 8.56 (d, J = 1.8 Hz, 1H), 8.35 (d, J = 1.8 Hz, 1H), 8.11 (s, 5H), 7.49 (br s, 1H), 3.84- 3.42 (m, 4H), 2.16-2.03 (m, 4H).MF-DH-46561.3% / 99.17%486.15 for C24H24F2N 4O3S / 487.2 (M + 1)δ 8.98 (d, J = 8.6 Hz, 1H), 8.66 (d, J = 1.8 Hz, 1H), 8.56-8.47 (m, 2H), 8.26 (d, J = 1.9 Hz, 1H), 8.19 (s, 1H), 6.89 (d, J = 3.9 Hz, 1H), 3.87-3.61 (m, 4H), 3.22- 3.19 (m, 3H), 2.15-2.02 (m, 4H), 1.69 (s, 6H).MF-DH-46716.8% / 99.17%427.18 for C22H23F2N 5O2 / 428.2 (M + 1)δ 8.56-8.50 (m, 1H), 8.44 (d, J = 2.0 Hz, 1H), 8.31-8.23 (m, 2H), 8.14-8.07 (m, 2H), 7.85 (br d, J = 7.8 Hz, 1H), 7.65 (t, J = 7.9 Hz, 1H), 6.84 (d, J = 3.7 Hz, 1H), 3.86-3.44 (m, 6H), 2.73-2.67 (m, 2H), 2.13-2.05 (m, 4H).MF-DH-46853.2% / 99.80%428.17 for C22H22F2N 4O3 / 429.2 (M + 1)d, J = 2.0 Hz, 1H), 8.29 (t, J = 1.8 Hz, 1H), 8.23 (d, J = 2.0 Hz, 1H), 8.13-8.07 (m, 2H), 7.86 (d, J = 7.9 Hz, 1H), 7.66 (t, J = 7.9 Hz, 1H), 6.85 (d, J = 3.8 Hz, 1H), 3.65-3.59 (m, 3H), 3.59- 3.51 (m, 4H), 3.39-3.34 (m, 2H), 2.14-2.02 (m, 4H).MF-DH-46941.5% / 96.50%386.12 for C19H16F2N 4O3 / 387.2 (M + 1)δ 13.62-13.07 (m, 1H), 9.09- 9.00 (m, 2H), 8.58-8.50 (m, 3H), 8.29-8.25 (m, 1H), 6.91 (d, J = 4.0 Hz, 1H), 3.82-3.49 (m, 4H), 2.16-2.01 (m, 4H).MF-DH-47024.3% / 99.63%424.41 for C21H18F2N 6O2 / 425.2 (M + 1)δ 9.35 (d, J = 2.6 Hz, 1H), 9.13 (d, J = 1.8 Hz, 1H), 9.05-9.02 (m, 1H), 8.49 (d, J = 1.9 Hz, 1H), 8.32-8.26 (m, 2H), 6.91 (d, J = 3.8 Hz, 1H), 3.76-3.48 (m, 4H), 2.74 (s, 3H), 2.14-2.01 (m, 4H).MF-DH-47146.3% / 99.45%424.15 for C19H16F2N 4O3 / 425.2 (M + 1)δ 9.39 (d, J = 2.4 Hz, 1H), 8.70 (dd, J = 2.6, 8.6 Hz, 1H), 8.49 (d, J = 2.0 Hz, 1H), 8.32-8.23 (m, 3H), 6.93 (d, J = 3.8 Hz, 1H), 3.65 (brd, J = 4.9 Hz, 4H), 2.72 (s, 3H), 2.16-2.00 (m, 4H).MF-DH-47252.8% / 98.32%428.1 for C21H19F2N 5O3 / 427.15 (M − 1)δ 8.90 (d, J = 2.2 Hz, 1H), 8.79 (d, J = 2.3 Hz, 1H), 8.61 (t, J = 2.3 Hz, 1H), 8.44 (d, J = 2.0 Hz, 1H), 8.25 (d, J = 2.0 Hz, 1H), 8.14 (d, J = 3.7 Hz, 1H), 6.88 (d, J = 3.7 Hz, 1H), 4.54 (t, J = 7.9 Hz, 2H), 4.25-4.15 (m, 2H), 3.78-3.48 (m, 4H), 2.15-2.01 (m, 4H).MF-DH-47712.4% / 99.8%413.17 for C21H19F2N 5O3 / 414.2 (M + 1)δ 9.01-8.95 (m, 2H), 8.71-8.66 (m, 1H), 8.57-8.51 (m, 2H), 8.46- 8.42 (m, 1H), 8.28-8.25 (m, 1H), 6.89 (d, J = 3.9 Hz, 1H), 3.78-3.50 (m, 4H), 3.38-3.33 (m, 2H), 2.15-2.03 (m, 4H), 1.17 (t, J = 7.2 Hz, 3H).MF-DH-47833.6% / 99.73%456.17 for C22H22F2N 6O3 / 457.2 (M + 1)δ 8.85 (d, J = 9.0 Hz, 1H), 8.71 (d, J = 2.5 Hz, 1H), 8.51 (d, J = 1.8 Hz, 1H), 8.44 (d, J = 3.8 Hz, 1H), 8.31-8.21 (m, 2H), 8.21- 8.11 (m, 3H), 6.86 (d, J = 3.9 Hz, 1H), 5.04-4.94 (m, 1H), 4.35- 4.28 (m, 1H), 3.97-3.93 (m, 1H), 3.83-3.69 (m, 4H), 3.34-3.27 (m, 2H), 2.15-2.02 (m, 4H).MF-DH-47925.6.5% / 94.32%456.17 for C22H22F2N 6O3 / 457.2 (M + 1)δ 8.93-8.89 (m, 1H), 8.77-8.73 (m, 1H), 8.68-8.65 (m, 1H), 8.45- 8.41 (m, 1H), 8.28-8.25 (m, 1H), 8.14 (br d, J = 3.7 Hz, 4H), 6.90 (d, J = 3.8 Hz, 1H), 5.06- 4.97 (m, 1H), 4.38-4.35 (m, 1H), 4.00-3.96 (m, 1H), 3.80-3.59 (m, 4H), 3.34-3.28 (m, 2H), 2.14-2.02 (m, 4H).MF-DH-48048.3% / 97.43%505.16 for C21H19F2N 5O3 / 506.2 (M + 1)δ 8.71-8.68 (m, 1H), 8.43 (s, 1H), 8.31 (s, 1H), 8.25 (s, 1H), 8.12-8.08 (m, 2H), 7.81-7.76 (m, 1H), 8.74-7.68 (m, 1H), 7.19-7.13 (m, 1H), 6.85 (s, 1H), 3.76-3.49 (m, 4H), 3.51-3.48 (m, 2H), 3.18-3.12 (m, 2H), 2.91 (s, 3H), 2.18-2.01 (m, 4H).MF-DH-48135.0% / 98.45%550.13 for C25H25ClF 2N4O4S / 551.2 (M + 1 )δ 8.62 (brd, J = 7.6 Hz, 1H), 8.47 (s, 1H), 8.32 (s, 2H), 8.25 (s, 1H), 8.22-8.14 (m, 1H), 7.91 (s, 1H), 6.87 (d, J = 3.5 Hz, 1H), 4.29- 4.19 (m, 1H), 3.75-3.50 (m, 4H), 3.35 (brs, 1H), 3.30-3.26 (m, 1H), 3.19-3.11 (m, 2H), 2.21- 2.03 (m, 8H).MF-DH-48261.4% / 99.74%419.1 for C19H16ClF 2N5O2 / 420.1 (M + 1)δ 9.36-9.21 (m, 1H), 9.03 (s, 1H), 8.74 (br s, 1H), 8.58-8.46 (m, 2H), 8.32-8.20 (m, 2H), 7.77 (br s, 1H), 3.86-3.44 (m, 4H), 2.09 (br s, 4H).MF-DH-48434.7% / 99.58%461.13 for C21H21F2N 5O3S / 462.2 (M + 1)δ 10.31 (s, 1H), 8.83 (s, 1H), 8.44 (br s, 2H), 8.33 (s, 1H), 8.25 (s, 1H), 8.14 (d, J = 3.8 Hz, 1H), 6.88 (d, J = 3.7 Hz, 1H), 3.77- 3.46 (m, 4H), 2.88-2.78 (m, 1H), 2.13-2.01 (m, 4H), 1.06-0.99 (m, 4H).MF-DH-48564.6% / 99.52%429.16 for C21H19F2N 5O3 / 430.2 (M + 1)δ 10.14-10.10 (m, 1H), 8.70 (d, J = 2.3 Hz, 1H), 8.62 (d, J = 2.2 Hz, 1H), 8.53 (s, 1H), 8.43 (d, J = 2.0 Hz, 1H), 8.24 (d, J = 2.0 Hz, 1H), 8.07 (d, J = 3.7 Hz, 1H), 6.86 (d, J = 3.7 Hz, 1H), 4.18 (d, J = 7.1 Hz, 2H), 3.76- 3.49 (m, 4H), 2.15-2.02 (m, 4H), 1.27 (t, J = 7.1 Hz, 3H).MF-DH-48623.4% / 99.55%481.19 for C25H25F2N 5O3 / 482.3 (M + 1)δ 8.44 (d, J = 1.8 Hz, 1H), 8.23 (d, J = 1.8 Hz, 1H), 8.15-7.97 (m, 3H), 7.68-7.54 (m, 2H), 7.44-7.31 (m, 1H), 6.99-6.96 (m, 1H), 6.85-6.81 (m, 1H), 4.42-4.24 (m, 1H), 3.74-3.46 (m, 6H), 2.24-2.02 (m, 5H), 1.93-1.76 (m, 3H).MF-DH-48741.8% / 99.22%427.18 for C22H23F2N 5O2 / 428.2 (M + 1)δ 9.04-8.99 (m, 1H), 8.58-8.53 (m, 1H), 8.47-8.40 (m, 1H), 8.27- 8.20 (m, 2H), 8.16-8.12 (m, 1H), 7.17-7.03 (m, 2H), 6.89- 6.85 (m, 1H), 3.79-3.54 (m, 4H), 2.13-2.04 (m, 4H), 1.58-1.55 (m, 6H).MF-DH-48917.5% / 96.47%482.18 for C25H24F2N 4O4 / 483.2 (M + 1)δ 12.77-12.14 (m, 1H), 8.44 (d, J = 2.0 Hz, 1H), 8.23 (d, J = 1.8 Hz, 1H), 8.14-8.06 (m, 2H), 7.99 (br d, J = 8.3 Hz, 1H), 7.69-7.62 (m, 1H), 7.54-7.48 (m, 1H), 6.83 (d, J = 3.7 Hz, 1H), 4.47-4.40 (m, 1H), 3.77-3.51 (m, 6H), 2.14-2.01 (m, 4H), 1.98- 1.83 (m, 3H).MF-DH-4958.1% / 95.00%420.11 for C18H18F2N 4O2 / 421.1 (M + 1)δ 8.46-8.41 (m, 2H), 8.25 (d, J = 2.1 Hz, 1H), 8.14-8.08 (m, 2H), 7.84-7.75 (m, 2H), 7.50 (s, 2H), 6.87 (d, J = 3.6 Hz, 1H), 3.77- 3.53 (m, 4H), 2.15-1.99 (m, 4H).MF-DH-49612.2% / 99.75%420.11 for C18H18F2N 4O2 / 421.1 (M + 1)δ 8.46 (d, J = 2.0 Hz, 1H), 8.24 (d, J = 2.0 Hz, 1H), 8.21-8.15 (m, 3H), 7.99 (d, J = 8.8 Hz, 2H), 7.44 (s, 2H), 6.88 (d, J = 3.7 Hz, 1H), 3.76-3.49 (m, 4H), 2.15- 2.02 (m, 4H).MF-DH-49721.0% / 99.02%488.13 for C23H22F2N 4O4S / 489.1 (M + 1)δ 8.46 (d, J = 2.0 Hz, 1H), 8.25 (d, J = 2.0 Hz, 1H), 8.16 (brd, J = 3.7 Hz, 3H), 7.74-7.68 (m, 1H), 7.58-7.53 (m, 1H), 6.86 (d, J = 3.7 Hz, 1H), 4.77 (s, 2H), 4.16- 4.09 (m, 2H), 3.77-3.57 (m, 4H), 3.52 (t, J = 7.2 Hz, 2H), 2.14- 2.04 (m, 4H).MF-DH-49844.0% / 99.46%490.19 for C26H24F2N 6O2 / 491.2 (M + 1)δ 8.49-8.42 (m, 2H), 8.24 (d, J = 2.1 Hz, 1H), 8.11 (br d, J = 3.4 Hz, 2H), 7.96-7.91 (m, 1H), 7.72-7.67 (m, 1H), 6.85 (d, J = 3.7 Hz, 1H), 6.70 (s, 2H), 3.74- 3.49 (m, 4H), 2.14-2.01 (m, 4H), 1.77-1.69 (m, 1H), 0.88-0.81 (m, 2H), 0.68-0.62 (m, 2H).MF-DH-49953.7% / 99.19%490.19 for C26H24F2N 6O2 / 491.2 (M + 1)δ 11.07-10.99 (m, 1H), 8.48- 8.41 (m, 2H), 8.28-8.16 (m, 3H), 8.00-7.94 (m, 1H), 7.74-7.65 (m, 2H), 6.89-6.83 (m, 1H), 6.67- 6.58 (m, 1H), 3.77-3.59 (m, 5H), 2.16-2.04 (m, 4H), 1.07- 1.00 (m, 2H), 0.97-0.92 (m, 2H).MF-DH-50046.0% / 99.61%491.19 for C25H23F2N 7O2 / 492.2 (M + 1)δ 11.26 (s, 1H), 9.41 (d, J = 2.3 Hz, 1H), 9.09 (d, J = 1.6 Hz, 1H), 8.90-8.86 (m, 1H), 8.49 (d, J = 1.8 Hz, 1H), 8.29-8.24 (m, 2H), 7.75 (d, J = 2.2 Hz, 1H), 6.92 (d, J = 3.7 Hz, 1H), 6.66 (d, J = 2.2 Hz, 1H), 3.68 (br dd, J = 7.3, 3.5 Hz, 5H), 2.08 (br s, 4H), 1.03 (br d, J = 3.8 Hz, 2H), 0.99-0.93 (m, 2H).MF-DH-50123.9% / 92.56%491.19 for C24H29F2N 5O3 / 492.2 (M + 1)δ 9.32 (d, J = 2.6 Hz, 1H), 9.06 (d, J = 1.7 Hz, 1H), 8.94 (t, J = 2.1 Hz, 1H), 8.47 (d, J = 1.8 Hz, 1H), 8.29-8.25 (m, 1H), 8.24- 8.20 (m, 1H), 6.91 (d, J = 3.7 Hz, 1H), 6.76 (s, 2H), 5.18 (s, 1H), 3.81-3.49 (m, 4H), 2.13-2.03 (m, 4H), 1.80-1.71 (m, 1H), 0.88- 0.83 (m, 2H), 0.70-0.66 (m, 2H).MF-DH-5023.5% / 96.91%483.12 for C19H15F2N 5O2 / 383.95 (M + 1)δ 13.13-12.91 (m, 1H), 8.64 (s, 1H), 8.41 (d, J = 1.6 Hz, 2H), 8.21 (d, J = 1.7 Hz, 1H), 7.93 (br s, 1H), 6.77 (d, J = 3.5 Hz, 1H), 3.84-3.51 (m, 4H), 2.12-2.00 (m, 4H).MF-DH-50762.5% / 97.07%385.12 for C20H17F2N 3O3 / 386.1 (M + 1)δ 13.39-12.96 (m, 1H), 8.50- 8.48 (m, 1H), 8.48-8.43 (m, 1H), 8.23 (d, J = 2.0 Hz, 1H), 8.14- 8.12 (m, 1H), 7.97-7.91 (m, 1H), 7.70 (t, J = 7.9 Hz, 1H), 6.84 (d, J = 3.7 Hz, 1H), 3.76-3.51 (m, 4H), 2.13-2.02 (m, 4H).MF-DH-50821.8% / 99.24%536.11 for C24H23ClF 2N4O4S / 537.2 (M + 1)δ 8.48 (d, J = 2.0 Hz, 1H), 8.24 (d, J = 1.9 Hz, 2H), 8.19-8.10 (m, 2H), 7.60-7.56 (m, 1H), 6.87 (d, J = 3.8 Hz, 1H), 4.11-3.94 (m, 2H), 3.86-3.46 (m, 6H), 3.39- 3.31 (m, 4H), 2.14-2.02 (m, 4H).MF-DH-50944.5% / 98.82%409.17 for C22H21F2N 5O / 409.95 (M + 1)δ 9.20 (d, J = 2.2 Hz, 1H), 8.77 (d, J = 2.1 Hz, 1H), 8.48-8.44 (m, 2H), 8.27-8.24 (m, 1H), 8.22- 8.19 (m, 1H), 6.89 (d, J = 3.7 Hz, 1H), 3.79-3.49 (m, 4H), 2.15-2.02 (m, 4H), 1.82 (s, 6H).MF-DH-51423.5% / 99.40%409.15 for C20H17F2N 7O / 410.1 (M + 1)δ 8.47 (d, J = 2.0 Hz, 1H), 8.28- 8.19 (m, 5H), 6.88 (d, J = 3.8 Hz, 1H), 3.79-3.53 (m, 4H), 2.15- 2.02 (m, 4H).MF-DH-5153.5% / 99.37%409.15 for C20H17F2N 7O / 410.1 (M + 1)δ 8.51 (t, J = 1.6 Hz, 1H), 8.45 (d, J = 2.0 Hz, 1H), 8.24 (d, J = 2.0 Hz, 1H), 8.10 (d, J = 3.6 Hz, 1H), 8.01 (d, J = 7.8 Hz, 1H), 7.92- 7.85 (m, 1H), 7.67 (t, J = 7.9 Hz, 1H), 7.15-7.00 (m, 1H), 6.85 (d, J = 3.6 Hz, 1H), 3.74-3.57 (m, 4H), 2.14-2.02 (m, 4H).MF-DH-5168.1% / 91.09%409.15 for C20H17F2N 7O / 410.1 (M + 1)δ 9.19-9.13 (m, 2H), 8.99-8.95 (m, 1H), 8.64-8.60 (m, 1H), 8.50- 8.46 (m, 1H), 8.27-8.24 (m, 2H), 6.91-6.88 (m, 1H), 5.77- 5.74 (m, 1H), 3.70-3.59 (m, 4H), 2.13-2.05 (m, 4H).MF-DH-5214.8% / 98.07%490.16 for C20H17F2N 7O / 491.1 (M + 1)δ 8.57-8.51 (m, 1H), 8.48 (d, J = 2.0 Hz, 1H), 8.33 (br d, J = 5.9 Hz, 2H), 8.20 (d, J = 3.8 Hz, 1H), 7.92-7.89 (m, 1H), 7.73- 7.67 (m, 1H), 6.89-6.86 (m, 1H), 4.54 (s, 1H), 3.76-3.54 (m, 4H), 3.29-3.25 (m, 2H), 2.16-2.03 (m, 4H), 1.15-1.11 (m, 6H).MF-DH-52711.0% / 99.12%472.14 for C23H22F2N 4O3S / 491.1 (M + 1)δ 8.47 (d, J = 2.0 Hz, 1H), 8.25 (d, J = 2.1 Hz, 1H), 8.19-8.12 (m, 2H), 8.10-8.05 (m, 1H), 7.72-7.67 (m, 1H), 7.5-7.51 (m, 1H), 6.86 (d, J = 3.7 Hz, 1H), 4.93-4.64 (m, 1H), 4.60-4.54 (m, 1H), 4.48-3.93 (m, 4H), 3.89-3.76 (m, 4H), 2.16-2.02 (m, 4H).MF-DH-1248.5% / 99.91%359.09 for C17H15ClF N5O / 360.0 (M + 1)δ 10.02 (d, J = 0.9 Hz, 1H), 8.67- 8.64 (m, 2H), 8.62-8.60 (m, 1H), 8.59-8.57 (m, 1H), 8.20 (d, J = 2.0 Hz, 1H), 5.04-4.85 (m, 1H), 3.84-3.44 (m, 4H), 2.06-1.74 (m, 4H).MF-DH-16649.1% / 95.19%373.11 for C18H17ClF N5O / 374.0 (M + 1)δ 9.80 (s, 1H), 8.60 (d, J = 1.8 Hz, 1H), 8.57-8.51 (m, 2H), 8.19 (d, J = 2.0 Hz, 1H), 5.05-4.84 (m, 1H), 3.82-3.38 (m, 4H), 2.58 (s, 3H), 2.04-1.71 (m, 4H).MF-DH-16951.1% / 99.91%373.11 for C18H17ClF N5O / 374.0 (M + 1)δ 9.26 (s, 2H), 8.51-8.49 (m, 1H), 8.46 (s, 1H), 8.17 (d, J = 2.0 Hz, 1H), 5.02-4.84 (m, 1H), 3.80-3.41 (m, 4H), 2.71 (s, 3H), 2.04-1.72 (m, 4H).MF-DH-17515.1% / 99.0%367.13 for C20H18FN3 O3 / 368.1 (M + 1)δ 8.37-8.35 (m, 1H), 8.15 (s, 1H), 7.93 (d, J = 3.3 Hz, 1H), 7.46 (s, 1H), 7.28 (br d, J = 8.8 Hz, 1H), 7.08 (d, J = 8.2 Hz, 1H), 6.75 (d, J = 3.3 Hz, 1H), 6.12 (s, 2H), 5.00-4.86 (m, 1H), 3.78-3.38 (m, 4H), 2.00-1.72 (m, 4H).MF-DH-17816.1% / 95.85%338.15 for C19H19FN4 O / 339.1 (M + 1)δ 9.18 (s, 1H), 9.14 (s, 2H), 7.71- 7.63 (m, 3H), 7.30-7.26 (m, 1H), 5.01-4.81 (m, 1H), 3.71-3.35 (m, 4H), 2.33 (d, J = 0.98 Hz, 3H), 1.99-1.81 (m, 2H), 1.79-1.65 (m, 2H).MF-DH-1809.1% / 99.31%338.15 for C19H19FN4 O / 339.1 (M + 1)δ 9.14 (d, J = 1.22 Hz, 1H), 8.59 (dd, J = 2.51, 1.53 Hz, 1H), 8.52- 8.47 (m, 2H), 8.10-8.07 (m, 1H), 7.68 (d, J = 1.10 Hz, 1H), 7.36 (dd, J = 8.62, 1.53 Hz, 1H), 5.02, 4.83 (m, 1H), 3.76, 3.38 (m, 4H), 2.35 (d, J = 0.73 Hz, 3H), 2.01-1.66 (m, 4H).MF-DH-1816.1% / 99.94%367.17 for C21H22FN3 O2 / 368.2 (M + 1)δ 8.48 (d, J = 1.8 Hz, 1H), 8.19- 8.10 (m, 3H), 8.03 (d, J = 1.7 Hz, 1H), 7.00 (d, J = 8.8 Hz, 2H), 5.03-4.84 (m, 1H), 3.89 (s, 3H), 3.80-3.76 (m, 3H), 3.72-3.43 (m, 4H), 2.03-1.71 (m, 4H).MF-DH-18610.6% / 99.77%411.20 for C23H26FN3 O3 / 412.1 (M + 1)δ 7.81 (s, 1H), 7.54 (d, J = 8.8 Hz, 2H), 7.51-7.33 (m, 1H), 7.23 (dd, J = 8.7, 2.8 Hz, 3H), 5.01- 4.85 (m, 1H), 3.88 (s, 3H), 3.73- 3.67 (m, 2H), 3.67-3.31 (m, 4H), 3.20 (s, 3H), 3.17-3.02 (m, 2H), 2.00-1.66 (m, 4H).MF-DH-18761.9% / 99.32%367.17 for C21H22FN3 O2 / 368.1 (M + 1)δ 7.81 (s, 1H), 7.54 (d, J = 8.8 Hz, 2H), 7.41-7.19 (m, 4H), 5.00- 4.85 (m, 1H), 3.88 (s, 3H), 3.75- 3.58 (m, 4H), 3.20 (s, 3H), 1.99- 1.68 (m, 4H).MF-DH-18912.6% / 99.27%352.16 for C21H21FN2 O2 / 353.1 (M + 1)δ 7.73 (s, 1H), 7.65 (d, J = 3.2 Hz, 1H), 7.55-7.43 (m, 3H), 7.28- 7.18 (m, 1H), 7.14 (d, J = 8.9 Hz, 2H), 6.73 (d, J = 3.2 Hz, 1H), 5.00-4.83 (m, 1H), 3.84 (s, 3H), 3.70-3.36 (m, 4H), 1.99-1.65 (m, 4H).MF-DH-19028.2% / 99.47%366.17 for C22H23FN2 O2 / 367.2 (M + 1)δ 7.66 (s, 1H), 7.49-7.41 (m, 4H), 7.22 (br d, J = 8.4 Hz, 1H), 7.12 (brd, J = 8.9 Hz, 2H), 5.01- 4.83 (m, 1H), 3.83 (s, 3H), 3.70- 3.46 (m, 4H), 2.33 (s, 3H), 1.99- 1.69 (m, 4H).MF-DH-19335.1% / 95.66%381.19 for C22H24FN3 O2 / 382.1 (M + 1)δ 7.68 (s, 1H), 7.47 (d, J = 8.80 Hz, 2H), 7.23 (dd, J = 8.19, 1.10 Hz, 1H), 7.21-7.14 (m, 2H), 7.14-7.04 (m, 1H), 5.01-4.82 (m, 1H), 3.86 (s, 3H), 3.70-3.36 (m, 4H), 2.72 (q, J = 7.54 Hz, 2H), 2.01-1.82 (m, 2H), 1.73 (br s, 2H), 1.24 (t, J = 7.46 Hz, 3H).MF-DH-19917.1% / 91.40%367.17 for C21H22FN3 O2 / 368.1 (M + 1)δ 8.51 (d, J = 1.34 Hz, 1H), 8.31 (s, 1H), 8.05 (d, J = 1.47 Hz, 1H), 7.87-7.78 (m, 2H), 7.32 (t, J = 7.95 Hz, 1H), 6.79 (dd, J = 8.13, 2.14 Hz, 1H), 5.04-4.85 (m, 1H), 3.90 (s, 3H), 3.81 (s, 3H), 3.75- 3.44 (m, 4H), 2.03-1.70 (m, 4H).MF-DH-20027.1% / 99.91%367.17 for C21H22FN3 O2 / 368.1 (M + 1)δ 8.57 (s, 1H), 8.52-8.40 (m, 1H), 8.37 (s, 1H), 8.34-8.25 (m, 1H), 7.28 (brd, J = 7.34 Hz, 1H), 7.13 (d, J = 8.19 Hz, 1H), 7.06 (t, J = 7.40 Hz, 1H), 5.04-4.87 (m, 1H), 3.97 (s, 3H), 3.88 (s, 3H), 3.79-3.51 (m, 4H), 2.04-1.72 (m, 4H).MF-DH-20417.1% / 97.52%353.15 for C20H20FN3 O2 / 354.1 (M + 1)δ 11.89 (brs, 1H), 8.51 (d, J = 1.47 Hz, 1H), 8.23 (d, J = 2.69 Hz, 1H), 8.09 (brd, J = 8.68 Hz, 2H), 8.06-7.96 (m, 1H), 7.01 (d, J = 8.80 Hz, 2H), 4.99-4.88 (m, 1H), 3.79 (s, 3H), 3.73-3.51 (m, 4H), 2.02-1.87 (m, 2H), 1.77 (br d, J = 2.08 Hz, 2H).MF-DH-20616.1% / 99.65%349.18 for C21H23N3 O2 / 350.2 (M + 1)δ 7.59 (s, 1H), 7.54-7.42 (m, 2H), 7.21-7.15 (m, 3H), 7.12-7.06 (m, 1H), 3.86 (s, 3H), 3.72-3.32 (m, 4H), 2.41 (s, 3H), 1.70-1.42 (m, 6H).MF-DH-2373.3% / 99.58%299.20 for C18H25N3 O / 300.3 (M + 1)δ 9.29 (s, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.80 (s, 1H), 7.47 (dd, J = 8.4, 1.2 Hz, 1H), 4.55 (brt, J = 7.2 Hz, 1H), 3.70-3.21 (m, 4H), 2.04-1.95 (m, 4H), 1.66-1.37 (m, 6H), 0.79-0.70 (m, 6H).MF-DH-24252.1% / 99.77%354.15 for C18H19FN4 O2 / 355.1 (M + 1)δ 8.23 (s, 1H), 7.87 (d, J = 8.6 Hz, 1H), 7.79 (d, J = 8.9 Hz, 2H), 7.66 (dd, J = 8.6, 1.2 Hz, 1H), 7.24 (d, J = 8.9 Hz, 2H), 5.03- 4.85 (m, 1H), 3.88 (s, 3H), 3.80- 3.35 (m, 4H), 2.02-1.68 (m, 4H).MF-DH-24324.1% / 99.17%336.16 for C19H21FN4 O / 337.2 (M + 1)δ 8.17 (s, 1H), 7.86 (d, J = 8.6 Hz, 1H), 7.79 (d, J = 8.9 Hz, 2H), 7.62 (dd, J = 8.6, 1.2 Hz, 1H), 7.24 (d, J = 8.9 Hz, 2H), 3.88 (s, 3H), 3.75-3.34 (m, 4H), 1.70- 1.44 (m, 6H).MF-DH-24548.2% / 98.74%335.16 for C20H21N3 O2 / 336.2 (M + 1)δ 8.39 (s, 1H), 7.91 (s, 1H), 7.75- 7.63 (m, 3H), 7.46 (dd, J = 8.7, 1.3 Hz, 1H), 7.15 (d, J = 8.9 Hz, 2H), 3.85 (s, 3H), 3.66-3.34 (m, 4H), 1.67-1.48 (m, 6H).MF-DH-24638.8% / 97.11%387.11 for C20H19ClF N3O2 / 388.1 (M + 1)δ 7.84 (s, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.68-7.63 (m, 2H), 7.63- 7.57 (m, 1H), 7.16 (br d, J = 8.9 Hz, 2H), 5.03-4.84 (m, 1H), 3.85 (s, 3H), 3.72-3.34 (m, 4H), 2.02-1.66 (m, 4H).MF-DH-24758.4% / 95.80%369.12 for C20H20ClN 3O2 / 370.1 (M + 1)δ 781-7.79 (m, 2H), 7.71-7.62 (m, 2H), 7.58-7.53 (m, 1H), 7.18-7.12 (m, 2H), 3.82 (s, 3H), 3.73-3.34 (m, 4H), 1.71-1.42 (m, 6H).MF-DH-24910.1% / 98.21%385.12 for C20H17F2N 3O3 / 386.2 (M + 1)δ 8.35 (s, 1H), 8.13 (s, 1H), 8.05- 7.98 (m, 2H), 7.78-7.76 (m, 1H), 7.62-7.58 (m, 1H), 6.81 (s, 1H), 3.70-3.35 (m, 4H), 1.68- 1.48 (m, 6H).MF-DH-27126.7% / 95.09%374.07 for C18H16C12 N4O / 375.0 (M + 1)δ 9.03 (d, J = 1.8 Hz, 1H), 8.75- 8.71 (m, 1H), 8.42 (s, 1H), 8.05 (d, J = 8.8 Hz, 1H), 7.83 (s, 1H), 7.64 (brd, J = 8.7 Hz, 1H), 3.71- 3.34 (m, 4H), 1.68-1.49 (m, 6H).MF-DH-27251.1% / 98.82%369.12 for C20H20ClN 3O2 / 370.2 (M + 1)δ 7.92 (d, J = 8.8 Hz, 1H), 7.79 (s 1H), 7.62-7.49 (m, 2H), 7.36- 7.26 (m, 2H), 7.04 (dd, J = 8.3, 2.3 Hz, 1H), 3.86 (s, 3H), 3.74- 3.33 (m, 4H), 1.69-1.45 (m, 6H).MF-DH-2846.6% / 97.83%347.18 for C19H23F2N 3O / 348.2 (M + 1)δ 8.29-8.27 (m, 1H), 8.00 (d, J = 1.9 Hz, 1H), 7.78-7.76 (m, 1H), 6.57-6.55 (m, 1H), 4.99-4.89 (m, 1H), 3.65-3.42 (m, 4H), 2.16 (br d, J = 19.6 Hz, 6H), 2.06- 1.99 (m, 2H), 1.64-1.51 (m, 6H).MF-DH-28760.4% / 99.06%349.18 for C21H23N3 O2 / 350.2 (M + 1)δ 8.07 (s, 1H), 7.87 (d, J = 3.7 Hz, 1H), 7.73 (d, J = 8.9 Hz, 2H), 7.10 (d, J = 8.9 Hz, 2H), 6.81 (d, J = 3.7 Hz, 1H), 3.82 (s, 3H), 3.75- 3.59 (m, 2H), 3.16 (br s, 2H), 2.47 (s, 3H), 1.60 (br s, 4H), 1.53-1.32 (m, 2H).MF-DH-28815.1% / 96.48%351.16 for C20H21N3 O3 / 352.2 (M + 1)δ 11.16-10.98 (m, 1H), 7.98- 7.92 (m, 1H), 7.73-7.63 (m, 3H), 7.11-7.05 (m, 2H), 6.91-6.86 (m, 1H), 3.82 (s, 3H), 3.43 (br s, 4H), 1.64-1.51 (m, 6H).MF-DH-28937.1% / 99.94%360.16 for C21H20N4 O2 / 361.1 (M + 1)δ 8.46 (s, 1H), 8.25 (d, J = 3.7 Hz, 1H), 7.70 (d, J = 8.9 Hz, 2H), 7.14 (d, J = 9.0 Hz, 2H), 6.94 (d, J = 3.7 Hz, 1H), 3.84 (s, 3H), 3.82-3.58 (m, 2H), 3.29-3.22 (m, 2H), 1.68-1.44 (m, 6H).MF-DH-29039.9% / 94.39%350.17 for C20H22N4 O2 / 351.2 (M + 1)δ 7.82-7.80 (m, 1H), 7.69 (d, J = 8.9 Hz, 2H), 7.50-7.48 (m, 1H), 7.06 (d, J = 9.0 Hz, 2H), 6.89- 6.86 (m, 1H), 6.47-6.43 (m, 2H), 3.81 (s, 3H), 3.51-3.44 (m, 4H), 1.63-1.51 (m, 6H).MF-DH-29219.3% / 99.93%340.11 for C18H17ClN 4O / 341.1 (M + 1)δ 9.06 (d, J = 2.1 Hz, 1H), 8.69 (d, J = 2.0 Hz, 1H), 8.56 (s, 1H), 8.41 (brd, J = 2.1 Hz, 1H), 8.05- 7.94 (m, 2H), 7.55 (br d, J = 8.7 Hz, 1H), 3.70-3.35 (m, 4H), 1.68-1.48 (m, 6H).MF-DH-33046.6% / 99.04%421.24 for C25H31N3 O3 / 422.3 (M + 1)1 δ 8.12-8.08 (m, 1H), 7.93 (d, J = 1.9 Hz, 1H), 7.35 (d, J = 8.9 Hz, 2H), 7.11 (d, J = 8.9 Hz, 2H), 6.46 (s, 1H), 4.22 (s, 1H), 3.85 (s, 3H), 3.68-3.46 (m, 4H), 2.69-2.65 (m, 2H), 1.69-1.51 (m, 8H), 1.04 (s, 6H).MF-DH-3893.5% / 99.81%331.14 for C19H17N5 O / 332.2 (M + 1)δ 9.44-9.36 (m, 1H), 8.70 (dd, J = 8.5, 2.1 Hz, 1H), 8.32 (s, 1H), 8.24-8.12 (m, 2H), 8.12-8.04 (m, 1H), 6.84 (d, J = 3.7 Hz, 1H), 3.59-3.25 (m, 4H), 1.58-1.38 (m, 6H).MF-DH-34634.2% / 99.29%366.19 for C21H23FN4 O / 367.1 (M + 1)δ 8.31 (s, 1H), 8.13 (s, 1H), 7.87- 7.83 (m, 1H), 7.58-7.53 (m, 2H), 6.91-6.85 (m, 2H), 6.72 (s, 1H), 5.03-4.82 (m, 1H), 3.78- 3.37 (m, 4H), 2.98 (s, 6H), 2.03- 1.65 (m, 4H).MF-DH-24124.2% / 89.16%335.16 for C20H21N3 O2 / 336.2 (M + 1)δ 8.48-8.46 (m, 1H), 7.78-7.76 (m, 1H), 7.66-7.56 (m, 3H), 7.14- 7.01 (m, 2H), 6.94-6.92 (m, 1H), 3.84 (s, 3H), 3.68-3.35 (m, 4H), 1.67-1.42 (m, 6H).MF-DH-42447.3% / 94.90%385.12 for C20H17F2N 3O3 / 386.2 (M + 1)δ 13.42-12.82 (m, 1H), 8.48- 8.46 (m, 1H), 8.26-8.20 (m, 1H), 8.18-8.06 (m, 5H), 6.86- 6.84 (m, 1H), 3.80-3.52 (m, 4H), 2.18-2.01 (m, 4H).MF-DH-42542.0% / 98.59%386.12 for C19H16F2N 4O3 / 387.2 (M + 1)δ 13.82-13.42 (m, 1H), 9.34- 9.32 (m, 1H), 9.04 (s, 1H), 8.88- 8.86 (m, 1H), 8.48 (s, 1H), 8.28- 8.22 (m, 2H), 6.90-6.88 (m, 1H), 3.82-3.52 (m, 4H), 2.18- 2.01 (m, 4H).MF-DH-47634.0% / 88.98%449.17 for C24H21F2N 5O2 / 450.2 (M + 1)δ 8.52 (d, J = 1.8 Hz, 1H), 8.32 (d, J = 1.8 Hz, 1H), 8.18-8.12 (m, 2H), 7.97 (d, J = 8.7 Hz, 2H), 5.74 (s, 1H), 3.83-3.44 (m, 4H), 2.14-2.03 (m, 4H), 1.39 (s, 6H).MF-DH-5178.0% / 96.91%449.18 for C23H21F2N 7O / 450.1 (M + 1)δ 13.97-13.91 (m, 1H), 9.13- 9.09 (m, 2H), 8.84-8.82 (m, 1H), 8.49-8.46 (m, 1H), 8.27-8.22 (m, 2H), 6.91-6.87 (m, 1H), 3.78- 3.53 (m, 4H), 2.18-2.05 (m, 5H), 1.13-0.98 (m, 4H).MF-DH-51812.0% / 96.52%449.18 for C13H21F2N 7O / 450.1 (M + 1)δ 14.15 (s, 1H), 9.41-9.13 (m, 1H), 8.66-8.41 (m, 2H), 8.31- 8.17 (m, 3H), 6.99-6.87 (m, 1H), 3.78-3.54 (m, 4H), 2.18-2.02 (m, 5H), 1.05-0.79 (m, 4H).MF-DH-5198.0% / 91.47%477.13 for C21H16F5N 7O / 478.1 (M + 1)δ 15.75-15.70 (m, 1H), 9.40- 9.38 (m, 1H), 8.76-8.70 (m, 1H), 8.51-8.49 (m, 1H), 8.36-8.30 (m, 2H), 8.29-8.27 (m, 1H), 6.96- 6.91 (m, 1H), 3.83-3.57 (m, 4H), 2.16-2.05 (m, 4H).MF-DH-52013.4% / 98.9%518.22 for C28H28F2N 6O2 / 519.2 (M + 1)δ 10.70-10.67 (m, 1H), 9.41- 9.39 (m, 1H), 9.13-9.11 (m, 1H), 8.89-8.83 (m, 2H), 8.50-8.48 (m, 1H), 8.29-8.26 (m, 2H), 8.15- 8.11 (m, 1H), 7.49-7.45 (m, 1H), 6.94-6.92 (m, 1H), 3.78- 3.54 (m, 4H), 2.15-2.02 (m, 4H), 1.33-1.32 (m, 9H).MF-DH-53843.0% / 94.34%471.20 for C25H27F2N 3O4 / 472.2 (M + 1)δ 12.46-12.12 (m, 1H), 8.21 (d, J = 2.0 Hz, 1H), 8.14 (d, J = 8.4 Hz, 2H), 8.07 (d, J = 2.0 Hz, 1H), 7.62 (d, J = 8.6 Hz, 2H), 6.56 (s, 1H), 4.22 (s, 1H), 3.75- 3.46 (m, 4H), 2.69-2.62 (m, 2H), 2.13-1.99 (m, 4H), 1.67-1.60 (m, 2H), 1.01 (s, 6H).MF-DH-54235.0% / 90.64%509.22 for C17H29F2N 5O3 / 510.2 (M + 1)δ 8.24-8.17 (m, 3H), 8.07 (d, J = 2.0 Hz, 1H), 7.69 (d, J = 8.7 Hz, 2H), 6.57 (s, 1H), 4.22 (s, 1H), 3.72-3.46 (m, 4H), 2.79-2.65 (m, 5H), 2.12-1.98 (m, 4H), 1.68-1.62 (m, 2H), 1.03-0.99 (m, 6H).MF-DH-54413.0% / 99.40%477.20 for C26H25F2N 5O / 478.2 (M + 1)δ 8.22-8.20 (m, 1H), 8.14-8.09 (m, 2H), 8.05-8.03 (m, 1H), 7.77- 7.72 (m, 2H), 3.81-3.52 (m, 4H), 3.44-3.37 (m, 2H), 2.13- 2.05 (m, 4H), 1.59-1.54 (m, 2H), 1.34 (s, 6H).MF-DH-56249.3% / 97.41%363.16 for C21H21N3 O3 / 364.2 (M + 1)δ 13.18-12.81 (m, 1H), 8.38 (d, J = 2.0 Hz, 1H), 8.19-8.09 (m, 6H), 6.86 (d, J = 3.8 Hz, 1H), 4.42-4.20 (m, 1H), 3.70-3.51 (m, 1H), 3.09-2.69 (m, 2H), 1.84-1.76 (m, 1H), 1.70-1.40 (m, 3H), 1.36-1.01 (m, 2H), 0.98-0.64 (m, 3H).MF-DH-574 (absolute stereochemistry not determined)43.6% / 99.22%334.12 for C19H15FN4 O / 335.1 (M + 1)δ 8.58 (brs, 1H), 8.38-8.25 (m, 3H), 8.25-8.18 (m, 1H), 8.05 (d, J = 8.8 Hz, 2H), 6.89 (d, J = 3.8 Hz, 1H), 5.50-5.23 (m, 1H), 4.06-3.58 (m, 4H), 2.27-2.02 (m, 2H).MF-DH-575 (absolute stereochemistry not determined)43.6% / 98.76%334.12 for C19H15FN4 O / 335.1 (M + 1)δ 8.58 (brs, 1H), 8.37-8.28 (m, 3H), 8.28-8.16 (m, 1H), 8.05 (d, J = 8.9 Hz, 2H), 6.89 (d, J = 3.8 Hz, 1H), 5.49-5.23 (m, 1H), 4.04-3.58 (m, 4H), 2.29-2.02 (m, 2H). Methods of UseIn one aspect, provided herein are methods for treating various disorders in a subject in need thereof, comprising administering to said subject a compound described herein. In some embodiments, the inhibitors of hydroxyprostaglandin dehydrogenase provided herein may be used for the prevention or treatment of a disease or a disorder that is associated with hydroxyprostaglandin dehydrogenase (such as 15-PGDH) and / or decreased levels of prostaglandins.In some embodiments, the inhibitors of hydroxyprostaglandin dehydrogenase provided herein may be used for the prevention or treatment of a disease or a disorder in which it is desirable to increase prostaglandin levels in the subject having said disease or disorder.

[0462] In some embodiments, the methods for treating the disorders comprises administering to said subject a 15-PGDH inhibitor. In some embodiments, a compound described herein is the 15-PGDH inhibitor. In some embodiments, a compound having Formula I, Formula II, or Formula III is the 15-PGDH inhibitor. In some embodiments, the methods comprise administering a therapeutically effective amount of a compound described herein. In some embodiments, the methods comprise administering a therapeutically effective amount of a compound having Formula I, Formula II, or Formula III. In some embodiments, the compound described herein is a 15-PGDH inhibitor. In some embodiments, the compound having Formula I, Formula II, or Formula III is a 15-PGDH inhibitor. In some embodiments, the administration takes place in vitro. In other embodiments, the administration takes place in vivo.

[0463] As used herein, a therapeutically effective amount of a 15-PGDH inhibitor refers to an amount sufficient to effect the intended application, including but not limited to, disease treatment, as defined herein. Also contemplated in the subject methods is the use of a sub-therapeutic amount of a 15-PGDH inhibitor for treating an intended disease condition.

[0464] The amount of the 15-PGDH inhibitor administered may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.

[0465] Measuring inhibition of biological effects of 15-PGDH can comprise performing an assay on a biological sample, such as a sample from a subject. Any of a variety of samples may be selected, depending on the assay. Examples of samples include, but are not limited to, blood samples (e.g. blood plasma or serum), exhaled breath condensate samples, bronchoalveolar lavage fluid, sputum samples, urine samples, and tissue samples.

[0466] A subject being treated with a 15-PGDH inhibitor may be monitored to determine the effectiveness of treatment, and the treatment regimen may be adjusted based on the subject's physiological response to treatment. For example, if inhibition of a biological effect of 15-PGDH is above or below a threshold, the dosing amount or frequency may be decreased or increased, respectively. The methods can further comprise continuing the therapy if the therapy is determined to be efficacious. The methods can comprise maintaining, tapering, reducing, or stopping the administered amount of a compound in the therapy if the therapy is determined to be efficacious. The methods can comprise increasing the administered amount of a compound in the therapy if it is determined not to be efficacious. Alternatively, the methods can comprise stopping therapy if it is determined not to be efficacious. In some embodiments, treatment with a 15-PGDH inhibitor is discontinued if inhibition of the biological effect is above or below a threshold, such as in a lack of response or an adverse reaction. The biological effect may be a change in any of a variety of physiological indicators.

[0467] In general, a 15-PGDH inhibitor is a compound that inhibits one or more biological effects of 15-PGDH. Such biological effects may be inhibited by about or more than about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more.

[0468] In some other embodiments, the subject methods are useful for treating a disease condition associated with 15-PGDH. Any disease condition that results directly or indirectly from an abnormal activity or expression level of 15-PGDH can be an intended disease condition.

[0469] In one aspect, provided herein is a method of promoting and / or stimulation skin pigmentation, comprising administering one or more of the compositions described herein to a subject in need thereof. Inhibitors of 15-PGDH are known to promote skin pigmentation (Markowitz et. al., WO 2015 / 065716). The hydroxyprostaglandin dehydrogenase inhibitors described herein can be used for promoting and / or inducing and / or stimulating pigmentation of the skin and / or skin appendages, and / or as an agent for preventing and / or limiting depigmentation and / or whitening of the skin and / or skin appendages, in particular as an agent for preventing and / or limiting canities. In some embodiments, the 15-PGDH inhibitors provided herein can be applied to skin of a subject, e.g., in a topical application, to promote and / or stimulate pigmentation of the skin and / or hair growth, inhibit hair loss, and / or treat skin damage or inflammation, such as skin damage caused by physical or chemical irritants and / or UV-exposure.

[0470] In another aspect, provided herein is a method of inhibiting hair loss, comprising administering one or more of the compositions described herein to a subject in need thereof. It is known that prostaglandins play an important role in hair growth. Prostaglandins such as prostaglandin A1, F2a and E2 are stored in hair follicles or adjacent skin environments and have been shown to be essential in maintaining and increasing hair density (Colombe L et. al, 2007, Exp. Dermatol, 16(9), 762-9). It has been reported that 15-PGDH, which is involved in the degradation of prostaglandins is present in the hair follicle dermal papillae, inactivates prostaglandins, especially, PGF2a and PGE2, to cause scalp damage and alopecia (Michelet J F et. al., 2008, Exp. Dermatol, 17(10), 821-8). Thus, the hydroxyprostaglandin dehydrogenase inhibitors described herein that have a suppressive or inhibitory activity against 15-PGDH can improve scalp damage, prevent alopecia and promote hair growth and be used in a pharmaceutical composition for the prevention of alopecia and the promotion of hair growth.

[0471] In another aspect, provided herein is a method of preventing and / or treating skin inflammation and / or damage, comprising administering one or more of the compositions described herein to a subject in need thereof.

[0472] In another aspect, provided herein is a method of preventing and / or treating vascular insufficiency, comprising administering one or more of the compositions described herein to a subject in need thereof. Prostaglandins including prostaglandin homologues produced in the body have been known to maintain the proper action of the blood vessel wall, especially to contribute to vasodilation for blood flow, preventing platelet aggregation and modulating the proliferation of smooth muscle that surrounds blood vessel walls (Yan. Cheng et. al., 2006, J. Clin., Invest). In addition, the inhibition of prostaglandins production or the loss of their activity causes the degeneration of the endothelium in the blood vessel walls, platelet aggregation and the dysfunction of cellular mechanism in the smooth muscle. Among others, the production of prostaglandins in blood vessels was shown to be decreased in hypertension patients, including pulmonary artery hypertension. the 15-PGDH inhibitors described herein can be used in a pharmaceutical composition for the prevention or the treatment of cardiovascular disease and / or diseases of vascular insufficiency, such as Raynaud's disease, Buerger's disease, diabetic neuropathy, and pulmonary artery hypertension.

[0473] In another aspect, provided herein is a method of preventing, treating, minimizing and / or reversing congestive heart failure, cardiomyopathy, comprising administering one or more of the compositions described herein to a subject in need thereof. In another aspect, provided herein is a method of reducing cardiac ejection fraction, comprising administering one or more of the compositions described herein to a subject in need thereof. It has been shown that administration of a 15-PGDH inhibitor can be used to treat, prevent, minimize, and / or reverse congestive heart failure, cardiomyopathy, and / or reduction of cardiac ejection fraction (Markowitz et. al., WO2018 / 187810). As such, the hydroxyprostaglandin dehydrogenase inhibitors described herein can be administered to a subject in need to treat, prevent, minimize and / or reverse congestive heart failure, cardiomyopathy, and / or reduction of cardiac ejection fraction.

[0474] In another aspect, provided herein is a method of preventing and / or treating a gastrointestinal disease, comprising administering one or more of the compositions described herein to a subject in need thereof. Prostaglandins are essential for maintaining the mechanism for protecting and defending gastric mucus membrane (Wallace J L., 2008, Physiol Rev., 88(4), 1547-65, S. J. Konturek et al., 2005, Journal of Physiology and Pharmacology, 56(5)). The inhibitors of hydroxyprostaglandin dehydrogenase described herein show a suppressive or inhibitory activity against 15-PGDH, which degrades prostaglandins that protect gastric mucus membranes. As such, the hydroxyprostaglandin dehydrogenase inhibitors can be effective for the prevention or the treatment of gastrointestinal diseases, inter alia, gastritis and gastric ulcer. In addition, the hydroxyprostaglandin dehydrogenase inhibitors provided herein may be used to prevent and / or treat other forms of intestinal injury including toxicity from radiation and / or chemotherapy, and chemotherapy-induced mucositis.

[0475] Additionally, it has been shown that administration of 15-PGDH inhibitors, alone or in combination with corticosteroids and / or TNF inhibitors can treat intestinal, gastrointestinal, or bowel disorders such as oral ulcers, gum disease, gastritis, colitis, ulcerative colitis, gastric ulcers, inflammatory bowel disease, and Crohn's disease (Markowitz et. al., WO 2018 / 102552). As such, the hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to treat and / or prevent treat intestinal, gastrointestinal, or bowel disorders such as oral ulcers, gum disease, gastritis, colitis, ulcerative colitis, gastric ulcers, inflammatory bowel disease, and Crohn's disease.

[0476] In another aspect, provided herein is a method of preventing and / or treating renal dysfunction, comprising administering one or more of the compositions described herein to a subject in need thereof. In the kidney, prostaglandins modulate renal blood flow and may serve to regulate urine formation by both renovascular and tubular effects. In clinical studies, inhibitors of prostaglandin have been used to improve creatinine clearance in patients with chronic renal disease, to prevent graft rejection and cyclosporine toxicity in renal transplant patients, to reduce the urinary albumin excretion rate and N-acetyl-beta-D-glucosaminidase levels in patients with diabetic nephropathy (Porter, Am., 1989, J. Cardiol., 64: 22E-26E). Furthermore, it has been reported that prostaglandins serve as vasodilators in the kidney, and, thus, the inhibition of prostaglandin production in the kidney results in renal dysfunction (Hao. C M, 2008, Annu Rev Physiol, 70, 357.about.77). The hydroxyprostaglandin dehydrogenase inhibitors described herein have a suppressive or inhibitory activity against 15-PGDH that degrades prostaglandins and can be used for the prevention and / or treatment of renal diseases that are associated with renal dysfunction.

[0477] In another aspect, provided herein is a method of stimulation bone resorption and bone formation, comprising administering one or more of the compositions described herein to a subject in need thereof. Prostaglandins have been shown to stimulate bone resorption and bone formation to increase the volume and the strength of the bone (H. Kawaguchi et. al., Clinical Orthop. Rel. Res., 313, 1995; J. Keller et al., Eur. Jr. Exp. Musculoskeletal Res., 1, 1992, 8692). Furthermore, inhibition of 15-PGDH increases callus size and mineralization after bone fracture (Collier et. al., ORS 2017 Annual Meeting Paper No. 0190). Considering that 15-PGDH inhibits the activities of prostaglandins as mentioned in the above, the inhibition of 15-PGDH activity may lead to the promotion of bone resorption and bone formation that are inhibited by 15-PGDH. Thus, the inhibitors of hydroxyprostaglandin dehydrogenase described herein can be effective for the promotion of bone resorption and bone formation by inhibiting 15-PGDH activity. The hydroxyprostaglandin dehydrogenase inhibitors provided herein can also be used to increase bone density, treat osteoporosis, promote healing of fractures, promote healing after bone surgery or joint replacement, and / or to promote healing of bone to bone implants, bone to artificial implants, dental implants, and bone grafts.

[0478] In another aspect, provided herein is a method of stimulating tissue regeneration by stimulating, comprising administering one or more of the compositions described herein to a subject in need thereof. Prostaglandin PGE2 supports expansion of several types of tissue stem cells. Inhibition of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), a prostaglandin-degrading enzyme, potentiates tissue regeneration in multiple organs. Studies show that inhibition of 15-PGDH increases prostaglandin PGE2 levels in bone marrow and other tissues; accelerates hematopoietic recovery following a bone marrow transplant; promotes tissue regeneration of colon and liver injury (Zhang, Y. et. al. Science 2015, 348 (6240)). The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used for tissue regeneration by supporting the expansion of tissue stem cells.

[0479] In another aspect, provided herein is a method of modulating cervical ripening, comprising administering one or more of the compositions described herein to a subject in need thereof. Prostaglandin E2 (PGE2) is a known cervical ripening agent that mediates EP2-receptor-signaling pathways in human cervical stromal cells; targets its own synthesis by increasing COX-2 and PTGES expression; and decreases its metabolism by loss of its degradative enzyme 15-PGDH (Word et. Al., WO2019010482) Downregulation of 15-PGDH was also found to be crucial for PGE2-induced cervical ripening and preterm birth. Modulation of 15-PDGH activity can be used to modulate cervical ripening; and induce or prevent preterm labor. The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to induce cervical ripening and labor, alone or in combination with another labor inducing agent.

[0480] In another aspect, provided herein is a method of promoting neuroprotection and / or stimulating neuronal regeneration, comprising administering one or more of the compositions described herein to a subject in need thereof. Prostaglandins, via their specific G protein coupled receptors, have a variety of physiological functions in the central nervous system. The major prostaglandin, prostaglandin E2 (PGE2) can activate receptor types EP1, 2, 3, and 4. Activation of EP2 and EP4 receptors can regulate adenylate cyclase and the generation of 3,5′-cyclic adenosine monophosphate (cAMP), whereas the activation of EP1 and EP3 receptors can regulate Ca2+ signaling. Studies show that the EP1 and EP2 receptors are expressed in neurons and microglia as well as neurons of the cerebral cortex, striatum, and hippocampus. In addition, activation of the EP2 receptor by PGE2 is involved in long-term synaptic plasticity and cognitive function (Chemtob et al. Semin Perinatol. 1994 February; 18(1):23-9; Yang et al., J Neurochem. 2009 January; 108(1):295-304). Studies also show that following activation, different PGE2 receptors can contribute or protect against N-methyl-D-aspartate (NMDA) neurotoxicity and ischemic stroke (Ahmad et al., Exp Transl Stroke Med. 2010 Jul. 8; 2(1):12). Other studies show that activation of the EP2 receptors protected neurons from amyloid β-peptide neurotoxicity in vitro (Echeverria et al., Eur J Neurosci. 2005 November; 22(9):2199-206). Several studies suggest that the mechanism by which PGE2 affords neuroprotection is through EP2 or EP4 receptors, as they both increases cAMP, followed by a protein kinase A (PKA)-dependent pathway (Echeverria et al. Eur J Neurosci. 2005 November; 22(9):2199-206; McCullough et al., J Neurosci. 2004 Jan. 7; 24(1):257-68). Stimulation of these receptors with PGE2 by administration of a compound that inhibits, reduces, and / or antagonizes 15-PGDH activity, such as the hydroxyprostaglandin dehydrogenase inhibitors that can inhibit 15-PGDH described herein, can promote neuroprotection in a subject from axonal degeneration, neuronal cell death, and / or glia cell damage after injury, augment neuronal signaling underlying learning and memory, stimulate neuronal regeneration after injury, and / or treat diseases, disorders, and / or conditions of the nervous system.

[0481] In another aspect, provided herein is a method of treating and / or preventing a neurological disorder, a neuropsychiatric disorder, a neural injury, a neural toxicity disorder, a neuropathic pain, or a neural degenerative disorder, comprising administering one or more of the compositions described herein to a subject in need thereof. In some embodiments, the disease, disorder, and / or condition of the nervous system, which can be treated with hydroxyprostaglandin dehydrogenase inhibitors provided herein, can include at least one of a neurological disorder, a neuropsychiatric disorder, a neural injury, a neural toxicity disorder, a neuropathic pain, or a neural degenerative disorder. For example, the neurological disorder can include at least one of traumatic or toxic injuries to peripheral or cranial nerves, spinal cord or brain, such as traumatic brain injury, stroke, cerebral aneurism, and spinal cord injury. The neurological disorder can also include at least one of Alzheimer's disease, dementias related to Alzheimer's disease, Parkinson's, Lewy diffuse body diseases, senile dementia, Huntington's disease, Gilles de la Tourette's syndrome, multiple sclerosis, amyotrophic lateral sclerosis, hereditary motor and sensory neuropathy, diabetic neuropathy, progressive supranuclear palsy, epilepsy, or Jakob-Creutzfieldt disease.

[0482] In some embodiments, the neural injury can be caused by or associated with at least one of epilepsy, cerebrovascular diseases, autoimmune diseases, sleep disorders, autonomic disorders, urinary bladder disorders, abnormal metabolic states, disorders of the muscular system, infectious and parasitic diseases, neoplasms, endocrine diseases, nutritional and metabolic diseases, immunological diseases, diseases of the blood and blood-forming organs, mental disorders, diseases of the nervous system, diseases of the sense organs, diseases of the circulatory system, diseases of the respiratory system, diseases of the digestive system, diseases of the genitourinary system, diseases of the skin and subcutaneous tissue, diseases of the musculoskeletal system and connective tissue, congenital anomalies, or conditions originating in the perinatal period.

[0483] In certain embodiments, the hydroxyprostaglandin dehydrogenase inhibitors can be administered to a subject or neurons of the subject to promote the survival, growth, development and / or function of the neurons, particularly, the central nervous system (CNS), brain, cerebral, and hippocampal neurons. In certain embodiments, the hydroxyprostaglandin dehydrogenase inhibitors can be used stimulate hippocampal neurogenesis, for the treatment of neuropsychiatric and neurodegenerative diseases, including (but not limited to) schizophrenia, major depression, bipolar disorder, normal aging, epilepsy, traumatic brain injury, post-traumatic stress disorder, Parkinson's disease, Alzheimer's disease, Down syndrome, spinocerebellar ataxia, amyotrophic lateral sclerosis, Huntington's disease, stroke, radiation therapy, chronic stress, and abuse of neuro-active drugs, such as alcohol, opiates, methamphetamine, phencyclidine, and cocaine.

[0484] In another aspect, provided herein is a method of treating and / or preventing fibrotic or adhesion disease, disorder or condition, comprising administering one or more of the compositions described herein to a subject in need thereof. It has been shown that inhibitors of short-chain dehydrogenase activity, such as 15-PGDH inhibitors, can be administered to a subject in need thereof to decrease fibrotic symptoms, such as collagen deposition, collagen accumulation, collagen fiber formation, inflammatory cytokine expression, and inflammatory cell infiltration, and treat and / or prevent various fibrotic diseases, disorders, and conditions characterized, in whole or in part, by the excess production of fibrous material, including excess production of fibrotic material within the extracellular matrix, or the replacement of normal tissue elements by abnormal, non-functional, and / or excessive accumulation of matrix-associated components (Markowitz et. al., WO2016 / 144958).

[0485] Fibrotic diseases, disorders and conditions characterized, in whole or in part, by excess production of fibrotic material can include systemic sclerosis, multifocal fibrosclerosis, nephrogenic systemic fibrosis, scleroderma (including morphea, generalized morphea, or linear scleroderma), sclerodermatous graft-vs-host-disease, kidney fibrosis (including glomerular sclerosis, renal tubulointerstitial fibrosis, progressive renal disease or diabetic nephropathy), cardiac fibrosis (e.g., myocardial fibrosis), pulmonary fibrosis (e.g. pulmonary fibrosis, glomerulosclerosis pulmonary fibrosis, idiopathic pulmonary fibrosis, silicosis, asbestosis, interstitial lung disease, interstitial fibrotic lung disease, and chemotherapy / radiation induced pulmonary fibrosis), oral fibrosis, endomyocardial fibrosis, deltoid fibrosis, pancreatitis, inflammatory bowel disease, Crohn's disease, nodular fasciitis, eosinophilic fasciitis, general fibrosis syndrome characterized by replacement of normal muscle tissue by fibrous tissue in varying degrees, retroperitoneal fibrosis, liver fibrosis, liver cirrhosis, chronic renal failure; myelofibrosis (bone marrow fibrosis), drug induced ergotism, myelodysplastic syndrome, myeloproliferative syndrome, collagenous colitis, acute fibrosis, organ specific fibrosis, and the like. The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to treat or prevent a fibrotic disease, disorder or condition.

[0486] The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to treat or prevent kidney fibrosis, including kidney fibrosis resulting from dialysis following kidney failure, catheter placement, a nephropathy, glomerulosclerosis, glomerulonephritis, chronic renal insufficiency, acute kidney injury, end stage renal disease or renal failure, or combinations thereof.

[0487] The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to treat or prevent liver fibrosis, including liver fibrosis resulting from a chronic liver disease, viral induced hepatic cirrhosis, hepatitis B virus infection, hepatitis C virus infection, hepatitis D virus infection, schistosomiasis, primary biliary cirrhosis, alcoholic liver disease or non-alcoholic steatohepatitis (NASH), NASH associated cirrhosis obesity, diabetes, protein malnutrition, coronary artery disease, auto-immune hepatitis, cystic fibrosis, alpha-1-antitrypsin deficiency, primary biliary cirrhosis, drug reaction and exposure to toxins, or combinations thereof.

[0488] The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to treat or prevent heart fibrosis such as cardiac fibrosis, endomyocardial fibrosis, idiopathic pulmonary fibrosis, and kidney fibrosis.

[0489] The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to treat or prevent systemic sclerosis.

[0490] The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to treat or prevent fibrotic diseases, disorders or conditions caused by post-surgical adhesion formation.

[0491] The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to reduce in intensity, severity, or frequency, and / or delay onset of one or more symptoms or features of a fibrotic disease, disorder or condition, or other related diseases, disorders or conditions.

[0492] The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to decrease or reduce collagen secretion, or collagen deposition, or collagen fiber accumulation, in a tissue or organ, such as the lung, the liver, the intestines, the colon, the skin or the heart, or a combination thereof.

[0493] Studies have shown that 15-PGDH inhibition ameliorates inflammatory pathology and fibrosis in pulmonary fibrosis (Smith et. al., bioRxiv 2019.12.16.878215; Barnthaler et. al., J. Allergy Clin. Immunol. 2019, 145 (3), 818-833). In some embodiments, the hydroxyprostaglandin dehydrogenase inhibitors described herein can be used to treat or prevent lung fibrosis, including pulmonary fibrosis, pulmonary hypertension, chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis, sarcoidosis, cystic fibrosis, familial pulmonary fibrosis, silicosis, asbestosis, coal worker's pneumoconiosis, carbon pneumoconiosis, hypersensitivity pneumonitides, pulmonary fibrosis caused by inhalation of inorganic dust, pulmonary fibrosis caused by an infectious agent, pulmonary fibrosis caused by inhalation of noxious gases, aerosols, chemical dusts, fumes or vapors, drug-induced interstitial lung disease, or pulmonary hypertension, and combinations thereof.

[0494] In another aspect, provided herein is a method of reducing and / or preventing scar formation, comprising administering one or more of the compositions described herein to a subject in need thereof. The hydroxyprostaglandin dehydrogenase inhibitors provided herein can used for reducing or preventing scar formation in a subject. The hydroxyprostaglandin dehydrogenase inhibitors provided herein can be used to reduce or prevent scar formation on skin or scleroderma.

[0495] In another aspect, provided herein is a method of treating and / or preventing muscle disorder, muscle injury and / or muscle atrophy, comprising administering one or more of the compositions described herein to a subject in need thereof. Studies have shown that inhibition of PGE2 degrading enzymes such as 15-PGDH, enable muscle regeneration and muscle repair after injury (Ho et al., PNAS 2017; Dong et al., Stem cell research and therapy 2020). The inhibitors of hydroxyprostaglandin dehydrogenase provided herein can be used to treat muscle disorder, muscle injury and / or muscle atrophy in a subject. In some cases, said subject suffering from a muscle disorder, muscle injury and / or muscle atrophy may have Duchenne muscular dystrophy (DMD), Becker muscular dystrophy, Fukuyama congenital muscular dystrophy (FCMD), limb girdle muscular dystrophy, congenital muscular dystrophy, facioscapulohumeral muscular dystrophy (FHMD), amyotrophic lateral sclerosis (ALS), distal muscular dystrophy (DD), an inherited myopathy, myotonic muscular dystrophy (MDD), oculopharyngeal muscular dystrophy, distal muscular dystrophy, Emery-Dreifuss muscular dystrophy, myotonia congenita, mitochondrial myopathy (DD), myotubular myopathy (MM), myasthenia gravis (MG), periodic paralysis, polymyositis, rhabdomyolysis, dermatomyositis, cancer cachexia, AIDS cachexia, stress induced urinary incontinence, urethral sphincter deficiency, sarcopenia, or a combination thereof.

[0496] In some embodiments, the inhibitors of hydroxyprostaglandin dehydrogenase provided herein can be used to treat sarcopenia. In another embodiment, the inhibitors of hydroxyprostaglandin dehydrogenase provided herein can be used to treat diaphragmatic atrophy or limb muscle atrophy due to the use of a mechanical ventilator. In some embodiments, the inhibitors of hydroxyprostaglandin dehydrogenase provided herein can be used to treat genetic disorders or neuromuscular disorders such as Spinal Muscular Atrophy (SMA). In some embodiments, the inhibitors of hydroxyprostaglandin dehydrogenase provided herein can be used to treat ptosis, rotator cuff muscle atrophy, immobilization related muscle atrophy, surgical procedure related muscle atrophy, sarcopenia, or a combination thereof.Pharmaceutical Compositions

[0497] The inhibitors of hydroxyprostaglandin dehydrogenase can be formulated into pharmaceutical compositions to treat diseases and disorders described herein. In some embodiments, a pharmaceutical composition may comprise a therapeutically effective amount of one or more inhibitors of hydroxyprostaglandin dehydrogenase provided herein.

[0498] The pharmaceutical composition described herein may be administered in such oral dosage forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, micronized compositions, granules, elixirs, tinctures, suspensions, ointments, vapors, liposomal particles, nanoparticles, syrups and emulsions. In some embodiments, the pharmaceutical composition may also be administered in intravenous (bolus or infusion), subcutaneous injection, suppository, intraperitoneal, topical (e.g., dermal epidermal, transdermal), ophthalmically such as ocular eyedrop, intranasally, subcutaneous, inhalation, intramuscular or transdermal (e.g., patch) form, all using forms well known to those of ordinary skill in the pharmaceutical arts.

[0499] In some embodiments, a compound provided herein can be administered as part of a therapeutic regimen that comprises administering one or more second agents (e.g. 1, 2, 3, 4, 5, or more second agents), either simultaneously or sequentially with the compound provided herein. When administered sequentially, the compound provided herein may be administered before or after the one or more second agents. When administered simultaneously, the compound provided herein and the one or more second agents may be administered by the same route (e.g. injections to the same location; tablets taken orally at the same time), by a different route (e.g. a tablet taken orally while receiving an intravenous infusion), or as part of the same combination (e.g. a solution comprising a compound provided herein and one or more second agents).

[0500] A combination treatment according to the disclosure may be effective over a wide dosage range. For example, in the treatment of adult humans, dosages from 0.01 to 1000 mg, from 0.5 to 100 mg, from 1 to 50 mg per day, and from 5 to 40 mg per day are examples of dosages that may be used. The exact dosage will depend upon the agent selected, the route of administration, the form in which the compound is administered, the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician.EXAMPLESExample 1: Synthesis and Characterization of Compounds

[0501] In another aspect, methods of making the inhibitors described herein are provided herein. In some cases, the inhibitors are isolated or extracted from one or more plants. In some cases, the inhibitors derived from the one or more plants may be further modified. In some cases, the inhibitors are further purified after isolation from the one or more plants.

[0502] Exemplary synthesis schemes for the inhibitors with phenyl core as described herein include:

[0503] Exemplary synthesis schemes for the inhibitors with 6-5 ring cores as described herein include:

[0504] In some cases, synthesis schemes may be entire synthesis schemes for producing the inhibitors provided herein. In other cases, synthesis schemes may be partial schemes for producing inhibitors provided herein.

[0505] Described herein are exemplary synthesis schemes that can be used to synthesize the inhibitors described herein. The following abbreviations are used:AbbreviationDescriptionAIBNazobisisobutyronitrileDCMdichloromethaneDIADdiisopropyl azodicarboxylateDIPEAN,N′-diisopropylethylamineDMAP4-dimethylaminopyridineDMFdimethylformamideEDCI1-ethy1-3-(3-dimethylaminopropyl)carbodiimideHATU1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxidehexafluorophosphateHOBthydroxybenzotriazolem-CPBAMeta-chloroperoxybenzoic acidNBSN-bromosuccinimideNCSN-chlorosuccinimideNISN-iodosuccinimidep-TSApara-toluenesulfonic acidTEAtriethylamineTFAtrifluoroacetic acidTHFtetrahydrofuranTPPtriphenylphosphinemmolMilli molarvolVolumegGramkgKilogramLLitremLMilli litre° C.Degree CelsiusTLCThin Layer ChromatographyHPLCHigh-performance liquid chromatographyLCMSLiquid chromatography - massspectrometryminMinuteshHoureqEquivalentsRTRoom temperatureRfRetention factorRPReversed phaseNMRNuclear magnetic resonancePpmParts per million Synthesis of benzimidazole-5-carboayamide Analogs with Amide Variation

[0506] Provided below is an exemplary scheme to synthesize benzimidazole-5-carboxyamide analogs with amide variation that are inhibitors of hydroxyprostaglandin dehydrogenase.

[0507] Step-1: Synthesis of methyl 4-fluoro-3-nitrobenzoate (Int-2): To a stirred solution of methyl 4-fluoro-3-nitrobenzoic acid (10 g, 54.02 mmol) in DCM (100 mL) were added oxalylchloride (9.42 mL, 108.04 mmol, 2 eq) and followed by the DMEF (1 mL) at 0° C. The RM was stirred at 0° C. for 1 h. The reaction was monitored by TLC, after completion of the reaction, quenched with methanol (20 mL), and stirred at room temperature for 1 h. Then solvent was evaporated under reduced pressure and diluted with ethyl acetate (100 mL), washed with sat.NaHCO3 solution (50 mL), and brine solution (50 mL), the organic phases are dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain methyl 4-fluoro-3-nitrobenzoate (10.4 g, 96.7%) as an off white solid. LCMS: 75.82%, m / z=199.8 [M+H]+; 1H NMR (CDCl3, 400 MHz): δ 8.75 (dd, J=2.20, 7.21 Hz, 1H), 8.32 (ddd, J=2.2, 4.3, 8.7 Hz, 1H), 7.39 (dd, J=8.7, 10.2 Hz, 1H), 3.97-3.99 (m, 3H).

[0508] Step-2: Synthesis of methyl 4-((3-chlorophenyl)amino)-3-nitrobenzoate (Int-3), (general procedure for SNAr reactions #1): In sealed bomb; To a stirred solution of methyl 4-fluoro-3-nitrobenzoate (10 g, 50.21 mmol, 1 eq) in EtOH (100 mL), 3-chloroaniline (7.68 g 60.25 mmol, 1.2 eq) was added at room temperature. Steel bomb cap was tightly closed and then resultant reaction mixture was heated to 100° C. for 16 h. The reaction was monitored by LCMS / TLC, after completion of the reaction cooled to room temperature, volatiles were evaporated, quenched with sat.NH4Cl (100 mL), extracted with EtOAc (3×50 mL), combined organic extracts were washed with brine (50 mL); dried over sodium sulfate, filtered and concentrated in vacuo to get crude, trituration with diethyl ether (100 mL) to obtained methyl 4-((3-chlorophenyl)amino)-3-nitrobenzoate (8.2 g, 53.24%) as a yellow solid. LCMS: 95.95%, m / z=307.1 [M+H]+; 1H NMR (CDCl3, 400 MHz): δ 9.73 (brs, 1H), 8.92 (d, J=2.1 Hz, 1H), 8.01 (dd, J=1.8, 8.9 Hz, 1H), 7.36-7.41 (m, 1H), 7.26-7.31 (m, 2H), 7.19 (d, J=8.9 Hz, 2H), 3.92 (s, 3H).

[0509] Step-3: Synthesis of methyl 3-amino-4-((3-chlorophenyl)amino)benzoate (Int-4), (general procedure for aryl nitro reduction using Fe): To a stirred solution of methyl 4-((3-chlorophenyl)amino)-3-nitrobenzoate (8.2 g, 26.79 mmol, 1 eq) in EtOH / water (1:1, 160 mL), iron powder (10.47 g, 187.55 mmol, 7 eq) and NH4Cl (10.03 g 187.55 mmol, 7 eq) were added at room temperature. The resultant reaction mixture was heated to 100° C. for 16 h. The reaction was monitored by LCMS / TLC and after completion, the reaction mixture was filtered through celite bed and washed with EtOAc (2×100 mL). Volatiles were evaporated, quenched with sat. NaHCO3 (100 mL), extracted with EtOAc (3×50 mL) and combined organic extracts were washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 50% EtOAc / heptane to obtained methyl 3-amino-4-((3-chlorophenyl) amino) benzoate (7.1 g, 96.07%) as a gummy liquid. LCMS: 67.71%, m / z=277.1 [M+H]+; 1H NMR (CDCl3, 400 MHz): δ 7.45-7.50 (m, 2H), 7.14-7.19 (m, 2H), 6.86-6.91 (m, 2H), 6.77 (td, J=1.2, 8.8 Hz, 1H), 5.55 (br s, 1H), 3.88 (s, 3H).

[0510] Step-4: Synthesis of methyl 1-(3-chlorophenyl)-1H-benzo[d]imidazole-5-carboxylate (Int-5): To a stirred solution of methyl 3-amino-4-((3-chlorophenyl)amino)benzoate (7.1 g, 25.72 mmol, 1 eq) and triethyl orthoformate (19.06 g, 128.62 mmol, 5 eq) in 1,4-Dioxane (80 mL) PTSA (884 mg, 5.144 mmol, 0.2 eq) was added at room temperature. The resulting reaction mixture was heated to 100° C. for 16 h until SM was consumed as indicated by crude LCMS / TLC. The reaction mixture was filtered through celite bed, washed with EtOAc (2×100 mL). Volatiles were evaporated, washed with sat. NaHCO3 (100 mL) and extracted with EtOAc (3×100 mL). The combined organic extracts were washed with brine (200 mL); dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 40% EtOAc / heptane to obtained methyl 1-(3-chlorophenyl)-1H-benzo[d]imidazole-5-carboxylate (5.8 g, 78.6%) as a pale brown solid. LCMS: 89.6%, m / z=287.2 [M+H]+; 1H NMR (CDCl3, 400 MHz): δ 8.60 (d, J=1.0 Hz, 1H), 8.18 (s, 1H), 8.08 (dd, J=1.5, 8.6 Hz, 1H), 7.53-7.58 (m, 3H), 7.42-7.51 (m, 2H), 3.97 (s, 3H).

[0511] Step-5: Synthesis of 1-(3-chlorophenyl)-1H-benzo[d]imidazole-5-carboxylic acid (Int-6), general procedure for ester hydrolysis using NaOH: To a stirred solution of methyl 1-(3-chlorophenyl)-1H-benzo[d]imidazole-5-carboxylate) (5.8 g, 20.23 mmol, 1 eq) in THF / water (8:2, 60 mL) or MeOH / water (8:2, 60 mL), NaOH (1.21 g, 30.34 mmol, 1.5 eq) was added room temperature and then continued stirring at room temperature for 16 h. The reaction was monitored by crude LCMS / TLC; after consumption of the starting material, volatiles were evaporated, neutralized with 1N HCl up to pH=7. The solids were filtered, washed with Et2O (200 mL) and dried in vacuo to obtain 1-(3-chlorophenyl)-1H-benzo[d]imidazole-5-carboxylic acid (4.5 g, 81.66%) as a pale brown solid. LCMS: 99.58%, m / z=273.1 [M+H]+; 1H NMR (DMSO-d6, 500 MHz): δ 12.44-13.20 (m, 1H), 8.73 (s, 1H), 8.32 (s, 1H), 7.96 (brd, J=8.6 Hz, 1H), 7.88 (s, 1H), 7.65-7.73 (m, 3H), 7.58-7.61 (m, 1H).

[0512] Step 6: General procedure for amide coupling using HATU: To a stirred solution of Int-6 (1 eq) in DMF (10 v) under inert atmosphere were added HATU (1.5 eq), Amine (1.2 eq) was added at 0° C. To this stirred solution N,N′-diisopropylethylamine (3 eq) was added at 0° C. and then continued for stirring at room temperature for 16 h. The reaction was monitored by crude LCMS / TLC; after consumption of the starting material, the reaction mixture was quenched with ice water (10 mL) and extracted with EtOAc (2×15 mL). The combined organic extracts were washed with ice water (2×10 mL) and brine (10 mL); dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 40% EtOAc / heptane, followed by prep-HPLC to obtain the products shown in Scheme 1.Synthesis of (3-aminopyrrolidin-1-yl) (1-(3-chlorophenyl)-1H-benzo[d]imidazol-5-yl) methanone

[0513] Provided below is an exemplary scheme to synthesize (3-aminopyrrolidin-1-yl) (1-(3-chlorophenyl)-1H-benzo[d]imidazol-5-yl) methanone that are inhibitors of hydroxyprostaglandin dehydrogenase.

[0514] Step-1: Synthesis of tert-butyl (1-(1-(3-chlorophenyl)-1H-benzo[d]imidazole-5-carbonyl)pyrrolidin-3-yl)carbamate (Int-7): Int-6 (400 mg, 1.47 mmol) was reacted with 3-Boc amino pyrrolidine (326 mg, 1.76 mmol, 1.2 eq) using the general procedure for amide coupling using HATU described above to afford tert-butyl (1-(1-(3-chlorophenyl)-1H-benzo[d]imidazole-5-carbonyl)pyrrolidin-3-yl)carbamate (280 mg, 43%) as a pale yellow liquid. LCMS: 81.8%, m / z=441.2 [M+H]+; 1H NMR (DMSO-d6, 400 MHz): δ 8.76 (s, 1H), 7.85-7.98 (m, 2H), 7.49-7.74 (m, 4H), 7.20-7.29 (m, 1H), 3.87-4.12 (m, 1H), 3.59-3.68 (m, 2H), 3.08-3.35 (m, 2H), 2.81-2.89 (m, 1H), 2.65-2.73 (m, 1H), 1.94-2.09 (m, 1H), 1.69-1.89 (m, 1H), 1.30-1.40 (m, 9H).

[0515] Step-2: Synthesis of (3-aminopyrrolidin-1-yl)(1-(3-chlorophenyl)-1H-benzo[d]imidazol-5-yl)methanone (MF-PGDH-051): To a stirred solution of Int-7 (280 mg, 0.63 mmol, 1 eq) in DCM (5 mL), cooled to 0° C. and added 4N HCl in 1,4-Dioxane (5 mL), allowed to warm to room temperature then continued stirring at room temperature for 16 h. The reaction was monitored by LCMS / TLC; after consumption of the starting material, the reaction mixture was concentrated and dissolved in water and washed with EtOAc (20 mL), then the aq. layer was basified with sat. NaHCO3 solution and extracted with EtOAc (3×20 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to afford (3-aminopyrrolidin-1-yl) (1-(3-chlorophenyl)-1H-benzo[d]imidazol-5-yl) methanone (120 mg, 57% yield) as an off-white solid. LCMS: m / z=341.2 [M+H]+.Synthesis of 1-(3-chlorophenyl)-N-cyclopropyl-N-methyl-1H-benzo[d]imidazole-5-carboxamide (MF-PGDH-064)

[0516] Provided below is an exemplary scheme to synthesize 1-(3-chlorophenyl)-N-cyclopropyl-N-methyl-1H-benzo[d]imidazole-5-carboxamide that are inhibitors of hydroxyprostaglandin dehydrogenase.

[0517] Step-1: Synthesis of 1-(3-chlorophenyl)-N-cyclopropyl-N-methyl-1H-benzo[d]imidazole-5-carboxamide (MF-PGDH-064): A stirred solution of 1-(3-chlorophenyl)-N-cyclopropyl-1H-benzo[d]imidazole-5-carboxamide (200 mg, 0.641 mmol, 1 eq) in DMF (3 mL) was cooled to 0° C. and NaH (60% in mineral oil)(24 mg, 0.96 mmol, 1.5 eq) added. After stirring at 0° C. for 20 min, methyl iodide (136.05 mg, 0.961 mmol, 1.5 eq) was added at 0° C. and allowed to warm to room temperature stirred for 6 h. The reaction was monitored by LCMS / TLC; after consumption of the starting material the reaction mixture was quenched with sat. ammonium chloride solution (20 mL) and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 40% EtOAc / heptane, followed by prep-HPLC purification to obtain 1-(3-chlorophenyl)-N-cyclopropyl-N-methyl-1H-benzo[d]imidazole-5-carboxamide (14.31 mg, 6.84% yield) as a brown liquid. LCMS: m / z=326.1 [M+H]+.Synthesis of 1-(1-(3-chlorophenyl)-1H-benzo[d]imidazole-5-carbonyl)pyrrolidin-3-one (MF-PGDH-090)

[0518] Provided below is an exemplary scheme to synthesize 1-(1-(3-chlorophenyl)-1H-benzo[d]imidazole-5-carbonyl) pyrrolidin-3-one that are inhibitors of hydroxyprostaglandin dehydrogenase.

[0519] Step-1 and 2: Synthesis of 1-(1-(3-chlorophenyl)-1H-benzo[d]imidazole-5-carbonyl)pyrrolidin-3-one (MF-PGDH-090): To a stirred solution of Int-6 (100 mg, 0.367 mmol, 1 eq) in DCM (2 mL), cool to 0° C. and added oxalyl chloride (92.73 mg, 0.735 mmol, 2.0 eq), DMF (0.1 mL), then stirred at 0° C. for 30 min. The reaction was monitored by TLC; after completion of the starting material the reaction mixture was concentrated and followed to the next step. Crude was dissolved in DCM (2 mL), cooled to 0° C., added pyrrolidone (53.60 mg, 121.5 mmol, 1.2 eq), warmed to room temperature then continued stirring at room temperature for 16 h. The reaction was monitored by crude LCMS / TLC; after consumption of the starting material the reaction mixture was concentrated in vacuo to obtain the crude. The crude was purified through prep-HPLC purification to obtain 1-(1-(3-chlorophenyl)-1H-benzo[d]imidazole-5-carbonyl) pyrrolidin-3-one (MF-PGDH-090, 4.8 mg, 3.85% yield) as a brown liquid.Synthesis of 1-(3-chlorophenyl)-1H-benzo[d]imidazole-5-carboxamide (MF-PGDH-102)

[0520] Provided below is an exemplary scheme to synthesize 1-(3-chlorophenyl)-1H-benzo[d]imidazole-5-carboxamide that are inhibitors of hydroxyprostaglandin dehydrogenase.

[0521] Step-1: Synthesis of 1-(3-chlorophenyl)-1H-benzo[d]imidazole-5-carboxamide (MF-PGDH-102): To a stirred solution of Int-6 (200 mg, 0.733 mmol, 1 eq) in DMF (5 mL) under inert atmosphere were added HATU (416 mg, 1.093 mmol, 1.5 eq), NH4Cl (196.33 mg, 3.669 mmol, 5.0 eq) was added at 0° C. To this stirred solution N,N′-diisopropylethylamine (282 mg, 2.177 mmol, 3.0 eq) was added at 0° C. and then continued for stirring at room temperature for 16 h. The reaction was monitored by crude LCMS / TLC; after completion of the starting material the reaction mixture was quenched with ice water (10 mL), extracted with EtOAc (2×15 mL). The combined organic extracts were washed with ice water (2×10 mL) and brine (10 mL); dried over sodium sulfate, filtered and concentrated in vacuo to obtained 1-(3-chlorophenyl)-1H-benzo[d]imidazole-5-carboxamide (138.52 mg, 69.51%) as an off-white solid. LCMS: m / z=272.1 [M+H]+.Synthesis of Benzimidazoles Analogs with 2-Substituents

[0522] Provided below is an exemplary scheme to synthesize benzimidazoles analogs with 2-substituents that are inhibitors of hydroxyprostaglandin dehydrogenase.

[0523] Step-1: Synthesis of 4-((3-chlorophenyl)amino)-3-nitrobenzoic acid (Int-1): To a stirred solution of (4-fluoro-3-nitrobenzoic acid (5 g, 27.02 mmol, 1 eq) in ethanol (100 mL) at room temperature, were added meta chloro aniline (4.18 g, 32.96 mmol, 1.22 eq) followed by the potassium carbonate (1.86 g, 13.51 mmol, 0.5 eq) and then heated to 80° C. for 16 h. The reaction was monitored by TLC, after completion of the reaction, cooled to room temperature and filtered; the solid was washed with ethanol and dried to obtain 4-((3-chlorophenyl)amino)-3-nitrobenzoic acid (5.2 g 65.8% yield) as an off white solid. LCMS: m / z=293.0[M+H]+.

[0524] Step-2: Synthesis of (4-((3-chlorophenyl)amino)-3-nitrophenyl)(piperidin-1-yl)methanone (Int-2): To a stirred solution of Int-1 (4.5 g, 15.41 mmol, 1 eq) in DCM (45 mL) was added oxalyl chloride (5.83 g, 46.23 mmol, 3 eq) drop-wise at 0° C., and then continued stirring at 0° C. for 1 h, The reaction was monitored by TLC. After completion of the reaction, it was cooled to room temperature and volatiles were evaporated. This was dissolved in DCM (45 mL) and to this stirred solution piperidine (1.57 g, 18.49 mmol, 1.2 eq) was added, stirred at room temperature for 5 h, concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 5% MeOH / DCM to obtain (4-((3-chlorophenyl) amino)-3-nitrophenyl)(piperidin-1-yl) methanone (5.7 g, 89% yield) as a yellow solid. LCMS: 87.89%, m / z=360.0[M+H]+.

[0525] Step-3: Synthesis of (3-amino-4-((3-chlorophenyl)amino)phenyl)(piperidin-1-yl)methanone (Int-3): To a stirred solution of Int-2 (7 g. 19.44 mmol, 1 eq) in EtOH:water (1:1, 120 mL), Iron powder (7.6 g 136.11 mmol, 7 eq) and NH4Cl (7.4 g 136.11 mmol, 7 eq) were added at room temperature. The resultant reaction mixture was heated to 90° C. for 16 h. The reaction was monitored by TLC; after consumption of the starting material, the reaction mixture was filtered through celite bed and washed with EtOAc (2×50 mL). Volatiles were evaporated, quenched with water (100 mL), extracted with EtOAc (3×100 mL). The combined organic extracts were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was triturated with diethyl ether (20 mL) to afford (3-amino-4-((3-chlorophenyl)amino) phenyl)(piperidin-1-yl)methanone (5 g, 77.60%) as a gummy liquid. LCMS: m / z=330.0 [M+H]+.

[0526] Step-4A: Synthesis of ethyl 1-(3-chlorophenyl)-5-(piperidine-1-carbonyl)-1H-benzo[d]imidazole-2-carboxylate (MF-PGDH-027): In a sealed tube; the stirred solution of Int-3 (200 mg, 0.606 mmol, 1 eq), ethyl glyoxalate (186.2 mg, 1.823 mmol, 3 eq) and PTSA (20 mg, 0.116 mmol, 0.2 eq) was added at room temperature. The resulting reaction mixture was heated to 70° C. for 16 h. The reaction was monitored by TLC; after completion of the starting material, cooled to room temperature and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 50% EtOAc / heptane, followed by Prep-HPLC purification to obtain MF-PGDH-027 (18.82 mg, 7.55% yield) as an off-white solid.

[0527] Step-4B: Synthesis of ethyl 2-(1-(3-chlorophenyl)-5-(piperidine-1-carbonyl)-1H-benzo[d]imidazol-2-yl)acetate (MF-PGDH-030): To a stirred solution of Int-3 (200 mg, 0.606 mmol, 1 eq) in DMF (3 mL), ethyl (E)-3-amino-3-ethoxyacrylate (355 mg, 1.818 mmol, 3 eq) was added at room temperature. The resulting reaction mixture was heated to 100° C. for 16 h. The reaction was monitored by TLC; after completion of the starting material, cooled to room temperature and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 50% EtOAc / heptane, followed by Prep-HPLC purification to obtain MF-PGDH-030 (35.4 mg, 13.7%) as an off-white solid.

[0528] Step-4C: Synthesis of MF-PGDH-091 (general procedure for ester hydrolysis using LiOH): To a stirred solution of MF-PGDH-30 (1 g 2.35 mmol, 1 eq) in THF:water (1:1, 10 mL) at 0° C., LiOH·H2O (235 mg, 4.7 mmol, 2 eq) was added at 0° C. The resultant reaction mixture was stirred at room temperature for 12 h. reaction was monitored by TLC; after completion of the starting material, cooled to room temperature and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 50% EtOAc / heptane, followed by Prep-HPLC purification to afford MF-PGDH-091 (20.38 mg, 2.9%) as an off-white solid. LCMS: m / z=354.2 [M+H]+.

[0529] Step-4D: Synthesis of methyl 4-((2-((3-chlorophenyl)amino)-5-(piperidine-1-carbonyl) phenyl) amino)-4-oxobutanoate (Int-4): Int-3 (500 mg, 1.51 mmol, 1 eq) was subjected to the general procedure for amide coupling with HATU to afford methyl 4-((2-((3-chlorophenyl)amino)-5-(piperidine-1-carbonyl)phenyl)amino)-4-oxobutanoate (600 mg, 89.1%) as an off-white solid. LCMS: m / z=444.1 [M+H]+.

[0530] Step-4E: Synthesis of ethyl 3-(1-(3-chlorophenyl)-5-(piperidine-1-carbonyl)-1H-benzo[d]imidazol-2-yl)propanoate (MF-PGDH-033) and 3-(1-(3-chlorophenyl)-5-(piperidine-1-carbonyl)-1H-benzo[d]imidazol-2-yl)propanoic acid (MF-PGDH-034): To a stirred solution of Int-4 (1 g, 2.252 mmol, 1 eq) in DCE (20 mL), TFA (10 mL) was added under inert atmosphere at 0° C. Slowly warmed to room temperature and then heated to 80° C. for 16 h. The reaction was monitored by TLC; after completion of the starting material the reaction mixture was cooled to room temperature and diluted with ice water (20 mL). Neutralized with 10% NaHCO3 solution and extracted with EtOAc (2×50 mL). The combined organic extracts were washed with ice water (2×10 mL) and brine (10 mL); dried over sodium sulfate, filtered and concentrated in vacuo to get crude. The crude was purified through Prep-HPLC purification to obtain MF-PGDH-033 (68.36 mg) and MF-PGDH-034 (33.41 mg) as off-white solids.

[0531] Step-4F: Synthesis of 3-(1-(3-chlorophenyl)-5-(piperidine-1-carbonyl)-1H-benzo[d]imidazol-2-yl)propanamide (MF-PGDH-035): To a stirred solution of MF-PGDH-034 (200 mg, 2.252 mmol, 1 eq) in steel bomb, aqueous ammonia (10 mL) in MeOH was added at 0° C.

[0532] The resulting reaction mixture was slowly warmed to room temperature and then heated to 80° C. for 16 h. The reaction was monitored by TLC; after completion of the starting material the reaction mixture was cooled to room temperature and concentrated in vacuo to get crude. The crude was purified through Prep-HPLC purification to obtain MF-PGDH-035 (33.27 mg, 17.3% yield) as an off-white solid.Synthesis of Benzimidazole-5-Carboxyamide Analogs with Aryl / Alkyl / Amide Variation

[0533] Provided below is an exemplary scheme to synthesize Benzimidazole-5-carboxyamide analogs with Aryl / alkyl / Amide variation that are inhibitors of hydroxyprostaglandin dehydrogenase.

[0534] The synthesis of Int-1 is described in 1a, Scheme 1 above.

[0535] Step-2: Synthesis of methyl 4-((4-methoxyphenyl)amino)-3-nitrobenzoate (Int-2): Methyl 4-fluoro-3-nitrobenzoate (10 g, 50.21 mmol, 1 eq) in EtOH (100 mL) was converted to Int-2 using the general procedure for SNAr reactions #1, with p-anisidine (7.68 g, 60.25 mmol, 1.2 eq) to afford methyl 4-((4-methoxyphenyl)amino)-3-nitrobenzoate (8.2 g, 53.24%) as a yellow solid. LCMS: 96.47%, m / z=303.1 [M+H]+.

[0536] Step-3: Synthesis of methyl 3-amino-4-((4-methoxyphenyl)amino)benzoate (Int-3): Methyl-(4-methoxyphenyl)amino)-3-nitrobenzoate (8.09 g, 26.79 mmol) was converted to methyl 3-amino-4-((4-methoxyphenyl)amino) benzoate (7.1 g, 96.07%) using the general procedure for aryl nitro reduction using Fe to afford Int-3 as a gummy liquid. LCMS: 91.32%, m / z=273.2 [M+H]+.

[0537] Step-4: Synthesis of methyl 1-(4-methoxyphenyl)-1H-benzo[d]imidazole-5-carboxylate / methyl 2-cyclopropyl-1-(4-methoxyphenyl)-1H-benzo[d]imidazole-5-carboxylate (Int-4a / 4b): To a stirred solution of methyl 3-amino-4-((4-methoxyphenyl)amino)benzoate (7.02 g, 25.72 mmol, 1 eq) and triethyl orthoformate / cyclopropinaldehyde (128.62 mmol, 5 eq) in 1,4-Dioxane (80 mL) / DMF, PTSA (884 mg, 5.144 mmol, 0.2 eq) / Na2S2O3 (1 eq) was added at room temperature.

[0538] The resulting reaction mixture was heated to 90° C. for 16 h until consumption of SM by crude LCMS / TLC. The reaction mixture was filtered through celite bed and washed with EtOAc (2×100 mL). Volatiles were evaporated, washed with sat. NaHCO3 (100 mL) and extracted with EtOAc (3×100 mL). The combined organic extracts were washed with brine (200 mL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 40% EtOAc / heptane to obtained methyl 1-(4-methoxyphenyl)-1H-benzo[d]imidazole-5-carboxylate, Int-4a (78.6% yield, m / z=283.3 [M+H]+) and methyl 2-cyclopropyl-3-(4-methoxyphenyl)-3H-imidazo[4,5-b]pyridine-6-carboxylate (Int-4b) (53.40% yield, m / z=323.33[M+H]+).

[0539] Step-5: Synthesis of 1-(4-methoxyphenyl)-1H-benzo[d]imidazole-5-carboxylic acid (Int-5a) / 2-cyclopropyl-1-(4-methoxyphenyl)-1H-benzo[d]imidazole-5-carboxylic acid (Int-5b): Int-4a / 4b (1 eq) was hydrolyzed using the general procedure for ester hydrolysis with NaOH to afford Int-5a (4.5 g, 81.66% yield, LCMS: m / z=269.2 [M+H]+), and Int-5b (230 mg, 64.5% yield, LCMS: m / z=309.0 [M+H]+) as a pale brown solid.

[0540] Step-6: Synthesis of MF-DH-008, MF-DH-009, and MF-DH-021: Int-5a / 5b were subjected to the general procedure for amide coupling with HATU to afford MF-DH-008, MF-DH-009, and MF-DH-021.Synthesis of Benzimidazole-5-Carboxyamide Analogs with Aryl / Amide Variation

[0541] Provided below is an exemplary scheme to synthesize benzimidazole-5-carboxyamide analogs with Aryl / alkyl / Amide variation that are inhibitors of hydroxyprostaglandin dehydrogenase.

[0542] The synthesis of Int-1 is described in Scheme 1.

[0543] Step-2: Synthesis of Int-2; general procedure for SNAr reaction #2: To a stirred solution of methyl 4-fluoro-3-nitrobenzoate (2.5 g, 12.51 mmol, 1 eq) in EtOH (100 mL) in a sealed bomb, 5-methoxypyridin-2-amine / 3-chloro-4-methoxyaniline (1.2 eq) and K2CO3 (1.726 g, 1 eq) were added at room temperature. The steel bomb was tightly sealed and the reaction mixture was heated to 100° C. for 16 h. The reaction was monitored by LCMS / TLC. Upon completion, the reaction mixture was cooled to room temperature and concentrated. The residue was quenched with sat.NH4Cl (100 mL) and extracted with EtOAc (3×50 mL), and the combined organic extracts were washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo to afford the crude. The crude was triturated with diethyl ether (100 mL) to afford Int-2a (50.5% yield, LCMS: m / z=304.1[M+H]+) for MF-PGDH-22 and MF-DH-141 as yellow solids.

[0544] Int-1 was converted to Int-2b (51.0% yield, m / z=337.2[M+H]+) for MF-PGDH-24 and MF-PGDH-61.

[0545] Int-1 was converted to Int-2c (59.0% yield, LCMS: m / z=317.1[M+H]+) for MF-PGDH-62 using the general procedure for SNAr #1.

[0546] Step-3: Synthesis of Int-3a, Int-3b, and Int-3c was accomplished using the general procedure for aryl nitro reduction to afford Int-3a (82.3% yield, LCMS: m / z=274.1 [M+H]+), Int-3b (79.2% yield, LCMS: m / z=307.1 [M+H]+) and Int-3c (80.0% yield, LCMS: m / z=287.2 [M+H]+) as gummy liquids.

[0547] Step-4: Synthesis of Int-4a, Int-4b, and Int-4c: To a stirred solution of Int-3a / Int-3b / Int-3c (1 eq) and triethyl orthoformate (19.06 g, 128.62 mmol, 5 eq) in 1,4-Dioxane (80 mL) / DMF, PTSA (884 mg, 0.2 eq) was added at room temperature. The resulting reaction mixture was heated to 90° C. for 16 h until consumption of SM by crude LCMS / TLC. The reaction mixture was filtered through celite bed, washed with EtOAc (2×50 mL). Volatiles were evaporated, washed with sat. NaHCO3 (20 mL); extracted with EtOAc (3×30 mL), combined organic extracts were washed with brine (30 mL); dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 40% EtOAc / heptane to obtain Int-4a (32.7% yield, LCMS: m / z=287.2 [M+H]+), Int-4b (73.0% yield, LCMS: m / z=317.1 [M+H]+), and Int-4c (83.0% yield, LCMS: m / z=297.0 [M+H]+) as pale brown solids.

[0548] Step-5: Synthesis of Int-5a, Int-5b, and Int-5c: Using the general procedure for ester hydrolysis with NaOH, Int-4a, Int-4b, and Int-4c were converted to Int-5a (65.2% yield, LCMS: m / z=270.1 [M+H]+), Int-5b (70.5% yield, LCMS: m / z=303.2 [M+H]+) and Int-5c (81.4% yield, LCMS: m / z=282.1 [M+H]+), all obtained as pale brown solids.

[0549] Step-6: Int-5 was coupled to the appropriate amines using the general procedure for amide couplings with HATU to afford MF-PGDH-022, MF-PGDH-024, MF-PGDH-062 and MF-DH-141.

[0550] Step-7: Synthesis of (1-(3-chloro-4-hydroxyphenyl)-1H-benzo[d]imidazol-5-yl)(piperidin-1-yl)methanone: To a stirred solution of (1-(3-chloro-4-methoxyphenyl)-1H-benzo[d]imidazol-5-yl)(piperidin-1-yl)methanone, MF-PGDH-024 (200 mg, 0.54 mmol, 1 eq) in CH2Cl2 (10 mL) under inert atmosphere; BBr3 (1.62 mL, 1.62 mmol, 3.0 eq, 1M in CH2Cl2) was added at 0° C. and stirred at room temperature for 16 h. The reaction was monitored by crude LCMS / TLC; after consumption of the starting material, the reaction mixture was quenched with MeOH (10 mL), evaporated to dryness and then quenched with saturated NaHCO3 solution (5 mL).

[0551] It was extracted with EtOAc (2×15 mL), combined organic extracts were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford the crude which was purified by prep-HPLC to afford 1-(3-chloro-4-hydroxyphenyl)-1H-benzo[d]imidazol-5-yl)(piperidin-1-yl)methanone, MF-PGDH-061 (120 mg, 63%) as off white solid.Synthesis of Pyrrolopyridine-5-Carboxyamide Analogs with Amide / Aryl / Hetero Aryl Variation

[0552] Provided below is an exemplary scheme to synthesize pyrrolopyridine-5-carboxyamide analogs with amide / Aryl / Hetero Aryl variations that are inhibitors of hydroxyprostaglandin dehydrogenase.Step 1, Scheme 9: As shown in Scheme 9, Int-1 was subjected to amide coupling with the appropriate amine using HATU as described previously to afford Int-2.

[0554] Piperidin-1-yl (1H-pyrrolo[2,3-b]pyridin-5-yl)methanone: (950 mg, Yield: 79%); LCMS: m / z=230.2 [M+H,]+; 1H NMR (400 MHz, DMSO-d6) δ=11.84 (s, 1H), 8.23 (s, 1H), 7.98 (s, 1H), 7.56 (d, J=1.83 Hz, 1H), 6.51 (d, J=1.89 Hz, 1H), 3.67-3.38 (m, 4H), 1.68-1.43 (m, 6H).

[0555] (4-fluoropiperidin-1-yl)(1H-pyrrolo[2,3-b]pyridin-5-yl)methanone: (2.17 g, Yield: 69%); LCMS: 88.5%, m / z=248.1 [M+H,]+; 1H NMR (400 MHz, DMSO-d6) δ=11.83 (s, 1H), 8.25 (s, 1H), 8.01 (s, 1H), 7.65 (d, J=1.84 Hz, 1H), 6.78 (d, J=1.86 Hz, 1H), 3.76-3.35 (m, 4H), 1.98-1.54 (m, 4H).

[0556] (3-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)(4-fluoropiperidin-1-yl)methanone: (1.15 g, Yield: 69%); LCMS: 85.2%) m / z=282 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ=13.11 (br s, 1H), 12.35 (s, 1H), 8.84 (s, 1H), 8.46 (s, 1H), 7.80 (s, 1H), 5.03-4.80 (m, 1H), 3.82-3.33 (m, 4H), 2.04-1.64 (m, 4H).

[0557] Step-2, Scheme 9: General Buchwald procedure for synthesis of (MF-PGDH-071 and MF-DH-123, 124): In sealed tube, a stirring solution of piperidin-1-yl(1H-pyrrolo[2,3-b]pyridin-5-yl) methanone / (4-fluoropiperidin-1-yl)(1H-pyrrolo[2,3-b]pyridin-5-yl)methanone (Int-2) (0.65 mmol, 1 eq) in dioxane (15 mL) under inert atmosphere, Cs2CO3 (422 mg, 1.3 mmol, 2.0 eq) and the corresponding chloro / bromo arene (1.2 eq) were added at room temperature. Argon gas was purged for 15 min then Xantphos (75.14 mg, 0.13 mmol, 0.2 eq) and Pd2(dba)3 (59.47 mg, 0.065 mmol, 0.1 eq)) were added under argon atmosphere. Sealed tube cap was tightly closed and the resultant reaction mixture was heated to 100° C. for 16 h. The reaction was monitored by crude LCMS / TLC; after completion of the reaction, the reaction mixture was quenched with satd. NH4Cl (10 mL), filtered through celite bed, washed with EtOAc (10 mL). The mixture was extracted with EtOAc (2×10 mL), combined organic extracts were washed with brine (10 mL), dried over sodium sulfate, filtered and concentrated in vacuo to obtain the crude. The crude was purified through silica gel column chromatography using 70% EtOAc / heptanes, followed by Prep-HPLC purification afforded MF-PGDH-071 and MF-DH-123, 124.

[0558] Step 1, Scheme 10: General procedure for chlorination using NCS. Synthesis of 3-chloro-1H-pyrrolo [2,3-b]pyridine-5-carboxylic acid (Int-2, Scheme 10): To a stirred solution of 1H-pyrrolo [2,3-b]pyridine-5-carboxylic acid (Int-1) (1 g, 6.17 mmol) in DMF (10 v) under inert atmosphere was added NCS (906 mg, 6.68 mmol) at 40° C. The resultant reaction mixture was heated to 60° C. for 4 h. The reaction was monitored by crude LCMS / TLC; after completion of the starting material the reaction mixture was quenched with ice water (20 mL), solids were filtered, washed with diethyl ether (3×10 mL). The crude product was azeotroped with toluene (2×10 mL) and then dried for 2 h to afford 3-chloro-1H-pyrrolo [2,3-b]pyridine-5-carboxylic acid (Int-2) as light brown solid (850 mg, Yield: 70%). LCMS: 88.2%) m / z=195.0 [M−H]−; 1H NMR (500 MHz, DMSO-d6) δ=13.18 (br s, 1H), 12.37 (s, 1H), 8.84 (s, 1H), 8.45 (s, 1H), 7.82 (s, 1H).

[0559] Step 2, Scheme 9 and Step 3, Scheme 10: General Ullmann coupling procedure: To a stirred solution of Int-2 (Scheme 9) / Int-3 (Scheme 10) (0.7 mmol, 1 eq) in Dioxane (100 mL), heteroaryl bromide (1.2 eq), K3PO4 (0.2 eq), CuI (0.2 eq), and trans-dimethylcyclohexane-1,2-diamine (0.2 eq), were added at room temperature. Reaction mixture was purged with argon gas for 15 min and then continued the reaction at 100° C. for 16 h. The reaction was monitored by TLC and after completion of the reaction, quenched with sat.NH4Cl solution (10 mL), and stirred at room temperature for 1 h. The solvent was evaporated under reduced pressure and diluted with ethyl acetate (10 mL), washed with sat. NaHCO3 solution (50 mL), and brine solution (50 mL) and the organic phase dried over sodium sulfate, filtered and concentrated under reduced pressure to afford crude product which was further purified by prep-HPLC to afford ...

Claims

1. A compound having the structure of Formula I:or a pharmaceutically acceptable salt thereof, wherein:X is selected from —OCH2—, —C(O)NH—, —NHC(O)—, —C(O)NMe-, —NMeC(O)—, —SCH2—, —S(O)CH2—, —SO2CH2—;each Y is independently selected from N and CR11;each R1 is independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, —NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;R2 is H and R3 is —CF3; orR2 and R3 are taken together to form oxo or thio;each R4 is independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, —NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;each R5 is independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, —NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;R6 and R7 are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl;each R8 is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;each R9 is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;each R10 is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3-10cycloalkyl;each R11 is independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, —NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;n is 0, 1, 2, 3, 4, or 5;m is 0, 1, 2, 3, or 4; andp is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;provided that said compound of Formula I is not2. A compound having the structure of Formula IIa:or a pharmaceutically acceptable salt thereof, wherein:T, U, and Y are independently selected from N and CR5;R1 is selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; wherein the alkyl, cycloalkyl, aryl, or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, —NR10SO2NR6R7, C1-6alkyl, C1-6 heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, and 5- to 10-membered heteroaryl;R2 is H and R3 is —CF3; orR2 and R3 are taken together to form oxo or thio;each R4 is independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR9, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, —NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; ortwo R4 are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4 are independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR9, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, —NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;each R5 is independently selected from H, halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR9, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, —NR10C(O)NR6R7, —NR10SO2R8, —NR10SO2NR6R7, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;R6 and R7 are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl;each R8 is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;each R9 is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;each R10 is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3-10cycloalkyl; andm is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; andp is 0, 1, or 2;provided that the compound is not3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein T is N and U is N.

4. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein T is N and U is CR5.

5. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein T is CR5 and U is N.

6. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein T is CR5 and U is CR5.

7. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein R2 and R3 are taken together to form oxo.

8. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein each R4 is independently selected from halo, —NR6R7, —OR8, —C(O)R9, —C(O)OR9, and —C(O)NR6R7.

9. The compound of claim 8, or a pharmaceutically acceptable salt thereof, wherein each R4 is halo.

10. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein two R4 are taken together with the carbon atoms to which they are attached and any intervening atoms to form a C3-10cycloalkyl, and any remaining R4 are each independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, and —C(O)NR6R7.

11. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein m is 0, 1, or 2.

12. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein each R5 is selected from halo, —NR6R7, —OR8, C1-6alkyl, and C1-6haloalkyl.

13. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein p is 0.

14. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein Y is N.

15. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein Y is CR5.

16. The compound of claim 2, wherein R1 is selected from C6-10aryl and 5- to 10-membered heteroaryl; wherein said aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, —NR6R7, —OR8, —C(O)R8, —C(O)OR8, —C(O)NR6R7, —SOR9, —SO2R9, —SO2NR6R7, —NR10C(O)R8, C1-6alkyl, C1-6haloalkyl, C3-10cycloalkyl, and 5- to 10-membered heteroaryl.

17. The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein R1 is C6-10 aryl, wherein the aryl is phenyl.

18. The compound of claim 16, or a pharmaceutically acceptable salt thereof, wherein R1 is 5- to 10-membered heteroaryl selected from isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl.

19. A compound having the structure of Formula III:or a pharmaceutically acceptable salt thereof, wherein:each X is independently selected from N and CR7;Y is selected from O, S, SO2, and C(R8)2;R1 is selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; wherein said alkyl, cycloalkyl, aryl, or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;R2 is H and R3 is —CF3; orR2 and R3 are taken together to form oxo or thio;R4 and R5 are independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl; wherein each alkyl, heteroalkyl, haloalkyl, and cycloalkyl is independently optionally substituted with 1 to 3 substituents independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; orR4 and R5 are taken together, along with the nitrogen atom to which they are attached, to form a 3- to 10-membered heterocycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6 haloalkyl, C3-10cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;each R6 is independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; ortwo R6's attached to the same carbon atom are taken together to form oxo, thio, or C3-10cycloalkyl, and any remaining R6's are independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6 heteroalkyl, C1-6haloalkyl, C3-10cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10 aryl, and 5- to 10-membered heteroaryl;each R7 is independently selected from H, halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;each R8 is independently selected from H, halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl; ortwo R8's can be taken together to form a C3-10cycloalkyl optionally substituted with 1 to 3 substituents independently selected from halo, —NR9R10, —OR11, —C(O)R11, —C(O)OR11, —C(O)NR9R10, —SOR12, —SO2R12, —SO2NR9R10, —NR13C(O)R11, —NR13C(O)NR9R10, —NR13SO2R11, —NR13SO2NR9R10, C1-6alkyl, C1-6heteroalkyl, C1-6 haloalkyl, C3-10 cycloalkyl, 3- to 10-membered heterocycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;R9 and R10 are independently selected at each occurrence from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, and C3-10cycloalkyl;each R11 is independently selected from H, C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10 cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;each R12 is independently selected from C1-6alkyl, C1-6heteroalkyl, C1-6haloalkyl, C3-10 cycloalkyl, C6-10aryl, and 5- to 10-membered heteroaryl;each R13 is independently selected from H, C1-6alkyl, C1-6haloalkyl, and C3-10 cycloalkyl;m is 1 or 2; andn is 0, 1, 2, 3, or 4.

20. The compound of claim 19, wherein the compound has the structure of Formula IIIc:or a pharmaceutically acceptable salt thereof.

21. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof of claim 1, and a pharmaceutically acceptable excipient.

22. A method of inhibiting 15-hydroxyprostaglandin dehydrogenase (15-PGDH) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof of claim 1.

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